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11,406	150% FOR PROOFREADING ® Uses I temporarily relieves minor aches and pains due to: headache, muscular aches, menstrual cramps, the common cold, backache, toothache, minor pain of arthritis. I temporarily reduces fever Warnings I Ask your doctor before use if you are pregnant, under a doctor’s care for a serious condition, age 60 or over, taking any other drug or have stomach problems. I This product may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: hives, facial swelling, asthma (wheezing), shock, skin reddening, rash, blisters. If an allergic reaction occurs, stop use and seek medical help right away. Do not use this product if you have ever had an allergic reaction to any pain reliever/fever reducer. I This product may cause stomach bleeding. I Long term continuous use of this product may increase risk of heart attack or stroke. Directions I do not take more than directed I the smallest effective dose should be used I do not take longer than 10 days, unless directed by a doctor I adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist I if pain or fever does not respond to 1 tablet, 2 tablets may be used I do not exceed 6 tablets in 24 hours, unless directed by a doctor I children under 12 years: ask a doctor Questions or comments? call toll free 1-800-88-ADVIL Wyeth Consumer Healthcare Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 10 Ibuprofen Tablets, 200 mg Pain Reliever/Fever Reducer (NSAID) READ AND KEEP CARD FOR COMPLETE WARNINGS AND INFORMATION (see also www.advil.com) UO151-10-2 DO NOT USE unless vial was sealed in unbroken plastic blister on cardboard card. DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date DRUG FACTS TEXT DEFINED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • BULLETS • SPACE BEFORE BULLET • WARNING BOX LINE TYPE SIZE 4.5 pt 4.5 pt 4.5 pt 3.5 pt 2 ems .5 pt REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Packaging Engineer Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed PANTONE 302 C Date 5/31/06 PASS # 1 Component # U0151-10-2 Drawing # 5174 Rev. # 1 Regulatory Manuscript Version: 7/27/05 Formula # WH# 0432-0033 PROCESS BLACK PROCESS YELLOW Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: Jeffrey M. Caruso SC: 5/31/06 Printer to Replace all FPO Codes with Scannable Art Job Information Identification Color Legend Vendor Identification Printer Notes ® Uses I temporarily relieves minor aches and pains due to: headache, muscular aches, menstrual cramps, the common cold, backache, toothache, minor pain of arthritis. I temporarily reduces fever Warnings I Ask your doctor before use if you are pregnant, under a doctor’s care for a serious condition, age 60 or over, taking any other drug or have stomach problems. I This product may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: hives, facial swelling, asthma (wheezing), shock, skin reddening, rash, blisters. If an allergic reaction occurs, stop use and seek medical help right away. Do not use this product if you have ever had an allergic reaction to any pain reliever/fever reducer. I This product may cause stomach bleeding. I Long term continuous use of this product may increase risk of heart attack or stroke. Directions I do not take more than directed I the smallest effective dose should be used I do not take longer than 10 days, unless directed by a doctor I adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist I if pain or fever does not respond to 1 tablet, 2 tablets may be used I do not exceed 6 tablets in 24 hours, unless directed by a doctor I children under 12 years: ask a doctor Questions or comments? call toll free 1-800-88-ADVIL Wyeth Consumer Healthcare Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 10 Ibuprofen Tablets, 200 mg Pain Reliever/Fever Reducer (NSAID) READ AND KEEP CARD FOR COMPLETE WARNINGS AND INFORMATION (see also www.advil.com) UO151-10-2 DO NOT USE unless vial was sealed in unbroken plastic blister on cardboard card. ACTUAL SIZE DATA MATRIX CODE = 01511002 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG FACTS TEXT DEFINED • DRUG FACTS TITLE • DRUG FACTS CONTINUED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • # OF CHARACTERS PER INCH • BULLETS • SPACE BEFORE BULLET • BARLINES, HAIRLINES • SPACE BETWEEN HAIRLINES AND BOX END TYPE SIZE 9 pt 8 pt 8 pt 6 pt 6.5 pt <39 5 pt 2 ems 1.5 pt, .5 pt 2 spaces PROCESS YELLOW PROCESS BLACK PANTONE 302 C Date 26-JAN-2007 PASS # 2 Component # U0151-12-3 Drawing # 6256 Rev. # 3 Regulatory Manuscript Version: 20-NOV-2006 Formula # FLF# 0432-0033.00 PANTONE WARM RED C Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: Printer to Replace all FPO Codes with Scannable Art Job Information Identification Color Legend Vendor Identification Printer Notes REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date OPEN OPEN HERE TO VIEW COMPLETE PRODUCT INFORMATION TEAR HERE TO OPEN Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) 10 Coated Tablets ® ADVIL® SAFETY SEALED ADVIL® SAFETY SEALED ADVIL® SAFETY SEALED DO NOT USE IF SEAL AROUND CAP IS BROKEN OR MISSING. Wyeth Consumer Healthcare, Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 Appearance of the brown Advil tablet is a trademark of Wyeth Consumer Healthcare See new warnings information Tablets U0151-12-3 Visit us at www.advil.com Drug Facts (continued) Stop use and ask a doctor if ■ you feel faint, vomit blood, or have bloody or black stools. These are signs of stomach bleeding. ■ pain gets worse or lasts more than 10 days ■ fever gets worse or lasts more than 3 days ■ stomach pain or upset gets worse or lasts ■ redness or swelling is present in the painful area ■ any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ do not take more than directed ■ the smallest effective dose should be used ■ do not take longer than 10 days, unless directed by a doctor (see Warnings) ■ adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist ■ if pain or fever does not respond to 1 tablet, 2 tablets may be used ■ do not exceed 6 tablets in 24 hours, unless directed by a doctor ■ children under 12 years: ask a doctor Other information ■ read all warnings and directions before use. ■ store at 20-25°C (68-77°F) ■ avoid excessive heat above 40°C (104°F) Inactive ingredients acetylated monoglycerides, beeswax and/or carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxides, lecithin, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, pregelatinized starch, propylparaben, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, titanium dioxide Questions or comments? call toll free 1-800-88-ADVIL Drug Facts Active ingredient Purpose (in each tablet) Pain reliever/ Ibuprofen 200 mg (NSAID).............. Fever reducer nonsteroidal anti-inflammatory drug Uses ■ temporarily relieves minor aches and pains due to: ■ headache ■ toothache ■ backache ■ menstrual cramps ■ the common cold ■ muscular aches ■ minor pain of arthritis ■ temporarily reduces fever Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: ■ hives ■ facial swelling ■ asthma (wheezing) ■ shock ■ skin reddening ■ rash ■ blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause stomach bleeding. The chance is higher if you: ■ are age 60 or older ■ have had stomach ulcers or bleeding problems ■ take a blood thinning (anticoagulant) or steroid drug ■ take other drugs containing an NSAID [aspirin, ibuprofen, naproxen, or others] ■ have 3 or more alcoholic drinks every day while using this product ■ take more or for a longer time than directed Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ right before or after heart surgery Ask a doctor before use if you have ■ problems or serious side effects from taking pain relievers or fever reducers ■ stomach problems that last or come back, such as heartburn, upset stomach, or stomach pain ■ ulcers ■ bleeding problems ■ high blood pressure ■ heart or kidney disease ■ taken a diuretic ■ reached age 60 or older Ask a doctor or pharmacist before use if you are ■ taking any other drug containing an NSAID (prescription or nonprescription) ■ taking a blood thinning (anticoagulant) or steroid drug ■ under a doctor's care for any serious condition ■ taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin ■ taking any other drug When using this product ■ take with food or milk if stomach upset occurs ■ long term continuous use may increase the risk of heart attack or stroke FPO 128 CODE FPO 01511203 OUTSIDE INSIDE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not use if blister is open or the words "ADVIL SAFETY SEALED" under blister are missing or torn. Pocket Pack Pocket Pack 10 Coated Tablets See new warnings information ® Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) READ AND KEEP CARD FOR COMPLETE WARNINGS AND INFORMATION (see also www.advil.com) BC136-4 Wyeth Consumer Healthcare, Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 Appearance of the brown Advil tablet is a trademark of Wyeth Consumer Healthcare Tablets Drug Facts (continued) ■ adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist ■ if pain or fever does not respond to 1 tablet, 2 tablets may be used ■ do not exceed 6 tablets in 24 hours, unless directed by a doctor ■ children under 12 years: ask a doctor Other information ■ read all warnings and directions before use. Keep card. ■ store at 20-25°C (68-77°F) ■ avoid excessive heat above 40°C (104°F) Inactive ingredients acetylated monoglycerides, beeswax and/or carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxides, lecithin, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, pregelatinized starch, propylparaben, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, titanium dioxide Questions or comments? call toll free 1-800-88-ADVIL 3 8 0573-0151-10 DRUG FACTS TEXT DEFINED • DRUG FACTS TITLE • DRUG FACTS CONTINUED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • # OF CHARACTERS PER INCH • BULLETS • SPACE BEFORE BULLET • BARLINES, HAIRLINES • SPACE BETWEEN HAIRLINES AND BOX END TYPE SIZE N/A 8 pt 8 pt 6 pt 6.5 pt <39 5 pt 2 ems 1.5 pt, .5 pt 2 spaces PROCESS CYAN PROCESS YELLOW PROCESS BLACK Date 25-JAN-2007 PASS # 3 Component # BC136-4 Drawing # 6307 Rev. # 2 Regulatory Manuscript Version: 17-JAN-2007 Formula # FLF# 0432-0033.00 PROCESS MAGENTA PANTONE 302 C Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: Printer to Replace all FPO Codes with Scannable Art BACKGROUND GRID IS 30% PANTONE 302 OVERPRINTING 100% CYAN Job Information Identification Color Legend Vendor Identification Printer Notes REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date .187 DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR BLUE ON UNPRINTED WHITE BACKGROUND DATA MATRIX CODE = 1364 1/8" Clear area around Data Matrix - Unprinted PRINTED AREA FOR LOT & EXP FOR LABEL POSITION ONLY This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DRUG FACTS TEXT DEFINED • DRUG FACTS TITLE • DRUG FACTS CONTINUED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • # OF CHARACTERS PER INCH • BULLETS • SPACE BEFORE BULLET • BARLINES, HAIRLINES • SPACE BETWEEN HAIRLINES AND BOX END TYPE SIZE 9 pt 8 pt 8 pt 6 pt 6.5 pt <39 5 pt 2 ems 1.5 pt, .5 pt 2 spaces PANTONE 302 C Date 23-JAN-2007 PASS # 1 Component # ML3660-2 Drawing # 6305 Rev. # 1 Regulatory Manuscript Version: 17-JAN-2007 Formula # FLF# 0432-0033.00 Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: Printer to Replace all FPO Codes with Scannable Art Job Information Identification Color Legend Vendor Identification Printer Notes REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date ML3660-2 LIFT HERE For More Drug Facts Drug Facts Active ingredient (in each tablet) Purpose Ibuprofen 200 mg (NSAID)* ..........................................Pain reliever/Fever reducer nonsteroidal anti-inflammatory drug Uses ■ temporarily relieves minor aches and pains due to: ■ headache ■ toothache ■ backache ■ menstrual cramps ■ the common cold ■ muscular aches ■ minor pain of arthritis ■ temporarily reduces fever Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: ■ hives ■ facial swelling ■ asthma (wheezing) ■ shock ■ skin reddening ■ rash ■ blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause stomach bleeding. The chance is higher if you: ■ are age 60 or older ■ have had stomach ulcers or bleeding problems ■ take a blood thinning (anticoagulant) or steroid drug Drug Facts (continued) ■ take other drugs containing an NSAID [aspirin, ibuprofen, naproxen, or others] ■ have 3 or more alcoholic drinks every day while using this product ■ take more or for a longer time than directed Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ right before or after heart surgery Ask a doctor before use if you have ■ problems or serious side effects from taking pain relievers or fever reducers ■ stomach problems that last or come back, such as heartburn, upset stomach, or stomach pain ■ ulcers ■ bleeding problems ■ high blood pressure ■ heart or kidney disease ■ taken a diuretic ■ reached age 60 or older Ask a doctor or pharmacist before use if you are ■ taking any other drug containing an NSAID (prescription or nonprescription) ■ taking a blood thinning (anticoagulant) or steroid drug ■ under a doctor’s care for any serious condition ■ taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin ■ taking any other drug Drug Facts (continued) When using this product ■ take with food or milk if stomach upset occurs ■ long term continuous use may increase the risk of heart attack or stroke Stop use and ask a doctor if ■ you feel faint, vomit blood, or have bloody or black stools. These are signs of stomach bleeding. ■ pain gets worse or lasts more than 10 days ■ fever gets worse or lasts more than 3 days ■ stomach pain or upset gets worse or lasts ■ redness or swelling is present in the painful area ■ any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ do not take more than directed ■ the smallest effective dose should be used ■ do not take longer than 10 days, unless directed by a doctor (see Warnings) 3/16" x 3/16" DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR DARK BLUE ON UNPRINTED WHITE BACKGROUND. DATA MATRIX CODE = 366002 PANEL 1 PANEL 2 BASE PANEL This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pocket Pack Pocket Pack 10 Coated Tablets 10 Coated Tablets Do not use if blister is open or the words "ADVIL SAFETY SEALED" under blister are missing or torn. See new warnings information See new warnings information ® Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) BC134-4 Wyeth Consumer Healthcare, Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 Appearance of the brown Advil tablet is a trademark of Wyeth Consumer Healthcare READ AND KEEP CARD FOR COMPLETE WARNINGS AND INFORMATION (see also www.advil.com) Tablets Drug Facts Active ingredient (in each tablet) Purpose Ibuprofen 200 mg (NSAID) ......Pain reliever/Fever reducer nonsteroidal anti-inflammatory drug Uses ■ temporarily relieves minor aches and pains due to: ■ headache ■ toothache ■ backache ■ menstrual cramps ■ the common cold ■ muscular aches ■ minor pain of arthritis ■ temporarily reduces fever Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: ■ hives ■ facial swelling ■ asthma (wheezing) ■ shock ■ skin reddening ■ rash ■ blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause stomach bleeding. The chance is higher if you: ■ are age 60 or older ■ have had stomach ulcers or bleeding problems ■ take a blood thinning (anticoagulant) or steroid drug ■ take other drugs containing an NSAID [aspirin, ibuprofen, naproxen, or others] ■ have 3 or more alcoholic drinks every day while using this product ■ take more or for a longer time than directed Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ right before or after heart surgery Ask a doctor before use if you have ■ problems or serious side effects from taking pain relievers or fever reducers ■ stomach problems that last or come back, such as heartburn, upset stomach, or stomach pain ■ ulcers ■ bleeding problems ■ high blood pressure ■ heart or kidney disease ■ taken a diuretic ■ reached age 60 or older Ask a doctor or pharmacist before use if you are ■ taking any other drug containing an NSAID (prescription or nonprescription) ■ taking a blood thinning (anticoagulant) or steroid drug ■ under a doctor’s care for any serious condition ■ taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin Drug Facts (continued) ■ taking any other drug When using this product ■ take with food or milk if stomach upset occurs ■ long term continuous use may increase the risk of heart attack or stroke Stop use and ask a doctor if ■ you feel faint, vomit blood, or have bloody or black stools. These are signs of stomach bleeding. ■ pain gets worse or lasts more than 10 days ■ fever gets worse or lasts more than 3 days ■ stomach pain or upset gets worse or lasts ■ redness or swelling is present in the painful area ■ any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ do not take more than directed ■ the smallest effective dose should be used ■ do not take longer than 10 days, unless directed by a doctor (see Warnings) ■ adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist ■ if pain or fever does not respond to 1 tablet, 2 tablets may be used ■ do not exceed 6 tablets in 24 hours, unless directed by a doctor ■ children under 12 years: ask a doctor Other information ■ read all warnings and directions before use. Keep card. ■ store at 20-25°C (68-77°F) ■ avoid excessive heat above 40°C (104°F) Inactive ingredients acetylated monoglycerides, beeswax and/or carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxides, lecithin, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, pregelatinized starch, propylparaben, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, titanium dioxide Questions or comments? call toll free 1-800-88-ADVIL 3 8 0573-0151-10 DRUG FACTS TEXT DEFINED • DRUG FACTS TITLE • DRUG FACTS CONTINUED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • # OF CHARACTERS PER INCH • BULLETS • SPACE BEFORE BULLET • BARLINES, HAIRLINES • SPACE BETWEEN HAIRLINES AND BOX END TYPE SIZE 9 pt 8 pt 8 pt 6 pt 6.25 pt <39 5 pt 2 ems 1.5 pt, .5 pt 2 spaces PROCESS CYAN PROCESS YELLOW PROCESS BLACK Date 24-JAN-2007 PASS # 1 Component # BC134-4 Drawing # 5832 Rev. # 2 Regulatory Manuscript Version: 17-JAN-2007 Formula # FLF# 0432-0033.00 PROCESS MAGENTA PANTONE 302 C Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: Printer to Replace all FPO Codes with Scannable Art BACKGROUND GRID IS 30% PANTONE 302 OVERPRINTING 100% CYAN Job Information Identification Color Legend Vendor Identification Printer Notes REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date .187 DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR BLUE ON UNPRINTED WHITE BACKGROUND DATA MATRIX CODE = 1344 .187 DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR BLUE ON UNPRINTED WHITE BACKGROUND DATA MATRIX CODE = 1344 1/8" Clear area around Data Matrix - Unprinted This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not use if blister is open or the words "ADVIL SAFETY SEALED" under blister are missing or torn. ® BC227-3 3 Vials of 10 Coated Tablets 3 Vials of 10 Coated Tablets Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) Ibuprofen Tablets, 200 mg Pain Reliever / Fever Reducer (NSAID) See new warnings information See new warnings information Wyeth Consumer Healthcare, Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 Appearance of the brown Advil tablet is a trademark of Wyeth Consumer Healthcare READ AND KEEP CARD FOR COMPLETE WARNINGS AND INFORMATION (see also www.advil.com) Tablets Home Home Office Office Car Car Drug Facts Active ingredient (in each tablet) Purpose Ibuprofen 200 mg (NSAID) ..... Pain reliever/Fever reducer *nonsteroidal anti-inflammatory drug Uses ■ temporarily relieves minor aches and pains due to: ■ headache ■ toothache ■ backache ■ menstrual cramps ■ the common cold ■ muscular aches ■ minor pain of arthritis ■ temporarily reduces fever Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: ■ hives ■ facial swelling ■ asthma (wheezing) ■ shock ■ skin reddening ■ rash ■ blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause stomach bleeding. The chance is higher if you: ■ are age 60 or older ■ have had stomach ulcers or bleeding problems ■ take a blood thinning (anticoagulant) or steroid drug ■ take other drugs containing an NSAID [aspirin, ibuprofen, naproxen, or others] ■ have 3 or more alcoholic drinks every day while using this product ■ take more or for a longer time than directed Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ right before or after heart surgery Ask a doctor before use if you have ■ problems or serious side effects from taking pain relievers or fever reducers ■ stomach problems that last or come back, such as heartburn, upset stomach, or stomach pain ■ ulcers ■ bleeding problems ■ high blood pressure ■ heart or kidney disease ■ taken a diuretic ■ reached age 60 or older Ask a doctor or pharmacist before use if you are ■ taking any other drug containing an NSAID (prescription or nonprescription) ■ taking a blood thinning (anticoagulant) or steroid drug ■ under a doctor’s care for any serious condition ■ taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin Drug Facts (continued) ■ taking any other drug When using this product ■ take with food or milk if stomach upset occurs ■ long term continuous use may increase the risk of heart attack or stroke Stop use and ask a doctor if ■ you feel faint, vomit blood, or have bloody or black stools. These are signs of stomach bleeding. ■ pain gets worse or lasts more than 10 days ■ fever gets worse or lasts more than 3 days ■ stomach pain or upset gets worse or lasts ■ redness or swelling is present in the painful area ■ any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ do not take more than directed ■ the smallest effective dose should be used ■ do not take longer than 10 days, unless directed by a doctor (see Warnings) ■ adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist ■ if pain or fever does not respond to 1 tablet, 2 tablets may be used ■ do not exceed 6 tablets in 24 hours, unless directed by a doctor ■ children under 12 years: ask a doctor Other information ■ read all warnings and directions before use. Keep card. ■ store at 20-25°C (68-77°F) ■ avoid excessive heat above 40°C (104°F) Inactive ingredients acetylated monoglycerides, beeswax and/or carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxides, lecithin, methylparaben, microcrystalline cellulose, pharmaceutical glaze, povidone, pregelatinized starch, propylparaben, simethicone, sodium benzoate, sodium lauryl sulfate, starch, stearic acid, sucrose, titanium dioxide Questions or comments? call toll free 1-800-88-ADVIL 3 9 0573-0151-13 DRUG FACTS TEXT DEFINED • DRUG FACTS TITLE • DRUG FACTS CONTINUED • HEADINGS • SUBHEADINGS/BODY TEXT • LEADING • # OF CHARACTERS PER INCH • BULLETS • SPACE BEFORE BULLET • BARLINES, HAIRLINES • SPACE BETWEEN HAIRLINES AND BOX END TYPE SIZE 9 pt 8 pt 8 pt 6 pt 6.25 pt <39 5 pt 2 ems 1.5 pt, .5 pt 2 spaces PROCESS CYAN PROCESS YELLOW PROCESS BLACK Date 08-FEB-2007 PASS # 3 Component # BC227-3 Drawing # 5944 Rev. # 2 Regulatory Manuscript Version: 17-JAN-2007 Formula # FLF# 0432-0033.00 PROCESS MAGENTA PANTONE 302 C Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: Printer to Replace all FPO Codes with Scannable Art BACKGROUND GRID IS 30% PANTONE 302 OVERPRINTING 100% CYAN Job Information Identification Color Legend Vendor Identification Printer Notes REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date 1/8" Clear area around Data Matrix - Unprinted .187 DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR BLUE ON UNPRINTED WHITE BACKGROUND DATA MATRIX CODE = 2273 .187 DATA MATRIX CODE (ECC200), PRINTED IN BLACK OR BLUE ON UNPRINTED WHITE BACKGROUND DATA MATRIX CODE = 2273 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIGITAL MECHANICAL COLOR REPRESENTATION MAY BE OFF FOLLOW COLOR LEGEND FOR ACTUAL COLOR. R E L E A S E D (1) (2) Date Date REVIEWED BY with DEPARTMENT PRINT NAME SIGNATURE DATE Changes Graphic Artist Labeling Compliance Medical Regulatory Affairs Marketing Legal Trademark Graphic Artist Closed PROCESS CYAN PROCESS YELLOW PROCESS BLACK Date 06/13/06 PASS # 2 Component # SL1179-2 Drawing # 6060 Rev. # 1 Regulatory Manuscript Version: N/A Formula # WH# N/A PROCESS MAGENTA PANTONE 302 C Graphics Development & Labeling Compliance Five Giralda Farms, Madison, NJ 07940 Phone: (973) 660-5000 • Fax: (973) 660-6048 Graphics Development & Labeling Compliance Graphic Artist: C. Weatherwalks SC: 06/05/06 PRINTER TO REPLACE FPO UPC'S WITH HI-RES DIGITAL ART ALSO PRINTER TO SUPPLY COLOR MATCHPRINT FOR COLOR APPROVAL PRIOR TO PRESS RUN. BACKGROUND GRID IS 30% PANTONE 302 OVERPRINTING 100% CYAN. Job Information Identification Color Legend Vendor Identification Printer Notes Contains: 1 Dozen, 10 Count Pocket Packs Wyeth Consumer Healthcare, Madison, NJ 07940 Made in USA U.S. Patent No. 5,087,454 Appearance of the brown Advil tablet is a trademark of Wyeth Consumer Healthcare SL1179-2 0151-12-2 Home Home Office Office Car Car minor arthritis pain headache backache muscle ache menstrual pain minor arthritis pain headache backache muscle ache menstrual pain This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.706386	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018989s067lbl.pdf', 'application_number': 18989, 'submission_type': 'SUPPL ', 'submission_number': 67}
11,410	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.791324	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19009s6lbl.pdf', 'application_number': 19009, 'submission_type': 'SUPPL ', 'submission_number': 6}
11,409	VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 1 of 20 TABLETS VASOTEC® (ENALAPRIL) Rx Only WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue Vasotec® as soon as possible. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity DESCRIPTION VASOTEC® (Enalapril Maleate) is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is: structural formula Enalapril maleate is a white to off-white, crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Enalapril maleate is supplied as 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the active ingredient enalapril maleate, each tablet contains the following inactive ingredients: lactose, magnesium stearate, sodium bicarbonate, and starch. The 10 mg and 20 mg tablets also contain iron oxides. CLINICAL PHARMACOLOGY Mechanism of Action Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 2 of 20 human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with VASOTEC alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with VASOTEC plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of VASOTEC remains to be elucidated. While the mechanism through which VASOTEC lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, VASOTEC is antihypertensive even in patients with low-renin hypertension. Although VASOTEC was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non- black patients. Pharmacokinetics and Metabolism Following oral administration of VASOTEC, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of VASOTEC is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 3 of 20 insufficiency (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min. Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. Pharmacodynamics and Clinical Effects Hypertension Administration of VASOTEC to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS). In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION). In some patients achievement of optimal blood pressure reduction may require several weeks of therapy. The antihypertensive effects of VASOTEC have continued during long term therapy. Abrupt withdrawal of VASOTEC has not been associated with a rapid increase in blood pressure. In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of VASOTEC, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. When given together with thiazide-type diuretics, the blood pressure lowering effects of VASOTEC are approximately additive. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC. In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC (see PRECAUTIONS, Drug Interactions). Heart Failure In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 4 of 20 heart size, and increased cardiac output and exercise tolerance. Heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. There was a beneficial effect on severity of heart failure as measured by the New York Heart Association (NYHA) classification and on symptoms of dyspnea and fatigue. Hemodynamic effects were observed after the first dose, and appeared to be maintained in uncontrolled studies lasting as long as four months. Effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year. Heart Failure, Mortality Trials In a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤35 percent were randomized to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment). Use of enalapril was associated with an 11 percent reduction in all-cause mortality and a 30 percent reduction in hospitalization for heart failure. Diseases that excluded patients from enrollment in the study included severe stable angina (>2 attacks/day), hemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine >2.5 mg/dL), cerebral vascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. The mortality benefit associated with enalapril does not appear to depend upon digitalis being present. A second multicenter trial used the SOLVD protocol for study of asymptomatic or minimally symptomatic patients. SOLVD-Prevention patients, who had left ventricular ejection fraction ≤35% and no history of symptomatic heart failure, were randomized to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. The majority of patients in the SOLVD- Prevention trial had a history of ischemic heart disease. A history of myocardial infarction was present in 80 percent of patients, current angina pectoris in 34 percent, and a history of hypertension in 37 percent. No statistically significant mortality effect was demonstrated in this population. Enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. Compared to placebo, 32 percent fewer patients receiving enalapril developed symptoms of overt heart failure. Hospitalizations for cardiovascular reasons were also reduced. There was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect. The SOLVD-Prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. However, under the conditions of follow-up in the SOLVD-Prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment. The SOLVD-Prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 5 of 20 In another multicenter, placebo-controlled trial (CONSENSUS) limited to patients with NYHA Class IV congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. The results are shown in the following table. SURVIVAL (%) Six Months One Year VASOTEC (n=127) 74 64 Placebo (n-126) 56 48 In both CONSENSUS and SOLVD-Treatment trials, patients were also usually receiving digitalis, diuretics or both. Clinical Pharmacology in Pediatric Patients A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered dose. Conversion of enalapril to enalaprilat was in the range of 63-76%. The overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults. In a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, VASOTEC was generally well tolerated. In the above pediatric studies, enalapril maleate was given as tablets of VASOTEC and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation (see Preparation of Suspension under DOSAGE AND ADMINISTRATION). INDICATIONS AND USAGE Hypertension VASOTEC is indicated for the treatment of hypertension. VASOTEC is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of VASOTEC and thiazides are approximately additive. Heart Failure VASOTEC is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients VASOTEC improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 6 of 20 PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), VASOTEC decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). In using VASOTEC consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that VASOTEC does not have a similar risk (see WARNINGS). In considering use of VASOTEC, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema). CONTRAINDICATIONS VASOTEC is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Do not co-administer aliskiren with Vasotec in patients with diabetes (see PRECAUTIONS, Drug Interactions). WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including VASOTEC) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including VASOTEC. This may occur at any time during treatment. In such cases VASOTEC should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 7 of 20 to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Excessive hypotension is rare in uncomplicated hypertensive patients treated with VASOTEC alone. Patients with heart failure given VASOTEC commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION). Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with VASOTEC in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS). In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 8 of 20 excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of VASOTEC, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of VASOTEC or concomitant diuretic may be necessary. Neutropenia/Agranulocytosis Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Fetal toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Vasotec as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue VASOTEC, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 9 of 20 has sustained irreversible injury. Closely observe infants with histories of in utero exposure to VASOTEC for hypotension, oliguria, and hyperkalemia. [see PRECAUTIONS, Pediatric use] No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD). PRECAUTIONS General Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including VASOTEC, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. (see PRECAUTIONS, Drug Interactions) In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when VASOTEC has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or VASOTEC may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassiumsparing diuretics, potassium supplements and/or potassium- Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 10 of 20 containing salt substitutes, which should be used cautiously, if at all, with VASOTEC (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to VASOTEC during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 11 of 20 NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Vasotec and other agents that affect the RAS. Do not co-administer aliskiren with Vasotec in patients with diabetes. Avoid use of aliskiren with Vasotec in patients with renal impairment (GFR <60 ml/min). Hypotension — Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of VASOTEC is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC. In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. Other Cardiovascular Agents: VASOTEC has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 12 of 20 Agents Increasing Serum Potassium: VASOTEC attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium- containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving VASOTEC. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant VASOTEC and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VASOTEC. Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Pregnancy Nursing Mothers Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to discontinue VASOTEC, taking into account the importance of the drug to the mother. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 13 of 20 Pediatric Use Neonates with a history of in utero exposure to VASOTEC: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfustions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. Antihypertensive effects of VASOTEC have been established in hypertensive pediatric patients age 1 month to 16 years. Use of VASOTEC in these age groups is supported by evidence from adequate and well-controlled studies of VASOTEC in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION). VASOTEC is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2, as no data are available. ADVERSE REACTIONS VASOTEC has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. VASOTEC has been found to be generally well tolerated in controlled clinical trials involving 2987 patients. For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with VASOTEC reporting adverse experiences was comparable to placebo. HYPERTENSION Adverse experiences occurring in greater than one percent of patients with hypertension treated with VASOTEC in controlled clinical trials are shown below. In patients treated with VASOTEC, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks. VASOTEC (n=2314) Incidence (discontinuation) Placebo (n=230) Incidence Body As A Whole Fatigue 3.0 (<0.1) 2.6 Orthostatic Effects 1.2 (<0.1) 0.0 Asthenia 1.1 (0.1) 0.9 Digestive Diarrhea 1.4 (<0.1) 1.7 Nausea 1.4 (0.2) 1.7 Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 14 of 20 Nervous/Psychiatric Headache 5.2 (0.3) 9.1 Dizziness 4.3 (0.4) 4.3 Respiratory Cough 1.3 (0.1) 0.9 Skin Rash 1.4 (0.4) 0.4 HEART FAILURE Adverse experiences occurring in greater than one percent of patients with heart failure treated with VASOTEC are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with VASOTEC and placebo, respectively. VASOTEC (n=673) Incidence (discontinuation) Placebo (n=339) Incidence Body As A Whole Orthostatic Effects 2.2 (0.1) 0.3 Syncope 2.2 (0.1) 0.9 Chest Pain 2.1 (0.0) 2.1 Fatigue 1.8 (0.0) 1.8 Abdominal Pain 1.6 (0.4) 2.1 Asthenia 1.6 (0.1) 0.3 Cardiovascular Hypotension 6.7 (1.9) 0.6 Orthostatic Hypotension 1.6 (0.1) 0.3 Angina Pectoris 1.5 (0.1) 1.8 Myocardial Infarction 1.2 (0.3) 1.8 Digestive Diarrhea 2.1 (0.1) 1.2 Nausea 1.3 (0.1) 0.6 Vomiting 1.3 (0.0) 0.9 Nervous/Psychiatric Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 15 of 20 Dizziness 7.9 (0.6) 0.6 Headache 1.8 (0.1) 0.9 Vertigo 1.6 (0.1) 1.2 Respiratory Cough 2.2 (0.0) 0.6 Bronchitis 1.3 (0.0) 0.9 Dyspnea 1.3 (0.1) 0.4 Pneumonia 1.0 (0.0) 2.4 Skin Rash 1.3 (0.0) 2.4 Urogenital Urinary Tract Infection 1.3 (0.0) 2.4 Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions). Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud's phenomenon. Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth. Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Musculoskeletal: Muscle cramps. Nervous/Psychiatric: Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality. Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis. Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity. Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 16 of 20 Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Angioedema: Angioedema has been reported in patients receiving VASOTEC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with VASOTEC should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS). Cough: See PRECAUTIONS, Cough. Pediatric Patients The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Clinical Laboratory Test Findings Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with VASOTEC alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of VASOTEC and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients. Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with VASOTEC but are rarely of clinical importance unless another cause Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 17 of 20 of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Liver Function Tests Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). OVERDOSAGE Limited data are available in regard to overdosage in humans. Single oral doses of enalapril above 1,000 mg/kg and ≥1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure). DOSAGE AND ADMINISTRATION Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of VASOTEC. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with VASOTEC to reduce the likelihood of hypotension (see WARNINGS). If the patient's blood pressure is not controlled with VASOTEC alone, diuretic therapy may be resumed. If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with VASOTEC alone, a diuretic may be added. Concomitant administration of VASOTEC with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS). Dosage Adjustment in Hypertensive Patients with Renal Impairment The usual dose of enalapril is recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 2.5 mg once daily. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily. Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 18 of 20 Renal Status Creatinine- Clearance mL/min Initial Dose mg/day Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80 >30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients* 2.5 mg on dialysis days† *See WARNINGS, Anaphylactoid reactions during membrane exposure †Dosage on nondialysis days should be adjusted depending on the blood pressure response. Heart Failure VASOTEC is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In the placebo-controlled studies that demonstrated improved survival, patients were titrated as tolerated up to 40 mg, administered in two divided doses. The recommended initial dose is 2.5 mg. The recommended dosing range is 2.5 to 20 mg given twice a day. Doses should be titrated upward, as tolerated, over a period of a few days or weeks. The maximum daily dose administered in clinical trials was 40 mg in divided doses. After the initial dose of VASOTEC, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of VASOTEC does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. Asymptomatic Left Ventricular Dysfunction In the trial that demonstrated efficacy, patients were started on 2.5 mg twice daily and were titrated as tolerated to the targeted daily dose of 20 mg (in divided doses). After the initial dose of VASOTEC, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of VASOTEC does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision (see DOSAGE AND ADMINISTRATION, Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions). The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 19 of 20 time of dosage adjustment there is not excessive hypotension or significant deterioration of renal function. The maximum daily dose is 40 mg. Pediatric Hypertensive Patients The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients). VASOTEC is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2, as no data are available. Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension) Add 50 mL of Bicitra®1 to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of VASOTEC and shake for at least 2 minutes. Let concentrate stand for 60 minutes. Following the 60-minute hold time, shake the concentrate for an additional minute. Add 150 mL of Ora- Sweet SF™2 to the concentrate in the PET bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days. Shake the suspension before each use. 1Registered trademark of Alza Corporation 2Trademark of Paddock Laboratories, Inc. HOW SUPPLIED VASOTEC Tablets, 2.5 mg, are white, oval shaped tablet imprinted with "VASO 2.5" and scored on one side and scored on the other. They are supplied as follows: NDC 0187-0140-30 bottles of 30 (with desiccant) NDC 0187-0140-90 unit of use bottles of 90 (with desiccant) VASOTEC Tablets, 5 mg, are white, rounded triangle shaped tablet imprinted with "VASO 5" on one side and scored on the other. They are supplied as follows: NDC 0187-0141-30 bottles of 30 (with desiccant) NDC 0187-0141-90 unit of use bottles of 90 (with desiccant) NDC 0187-0141-10 bottles of 1,000 (with desiccant) VASOTEC Tablets, 10 mg, are rust red, rounded triangle shaped tablet imprinted with "VASO 10" on one side and scored on the other. They are supplied as follows: NDC 0187-0142-30 bottles of 30 (with desiccant) NDC 0187-0142-90 unit of use bottles of 90 (with desiccant) Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASOTEC ® TABLETS (ENALAPRIL) NDA 018998 Proposed Labeling Page 20 of 20 NDC 0187-0142-10 bottles of 1,000 (with desiccant) VASOTEC Tablets, 20 mg, are peach, rounded triangle shaped tablet imprinted with "VASO 20" on one side and scored on the other. They are supplied as follows: NDC 0187-0143-30 bottles of 30 (with desiccant) NDC 0187-0143-90 unit of use bottles of 90 (with desiccant) NDC 0187-0143-10 bottles of 1,000 (with desiccant) Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided. Vasotec® is a registered trademark of Valeant International (Barbados) SRL Manufactured in Canada by: Valeant Pharmaceuticals International, Inc. Steinbach, MB R5G 1Z7 Canada For: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA Rev. TBD Reference ID: 3188614 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:11.806549	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018998s077lbl.pdf', 'application_number': 18998, 'submission_type': 'SUPPL ', 'submission_number': 77}
11,411	Structural Formula LUPRON® INJECTION (leuprolide acetate) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L prolinamide acetate (salt) with the following structural formula: LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption Bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In a controlled study comparing LUPRON 1 mg/day given subcutaneously to DES (diethylstilbestrol), 3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The objective response to treatment was also similar for the two groups. INDICATIONS AND USAGE LUPRON INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced prostatic cancer. CONTRAINDICATIONS 1. LUPRON INJECTION is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION: Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS Initially, LUPRON, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LUPRON treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON, pregnancy must be excluded (see CONTRAINDICATIONS section). Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. PRECAUTIONS Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS sections). Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Information for Patients See INFORMATION FOR PATIENTS which appears after the REFERENCE section. Laboratory Tests Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Pediatric Use See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children with central precocious puberty. Geriatric Use In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases. Potential exacerbation of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction. In a comparative trial of LUPRON INJECTION (leuprolide acetate) versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded. LUPRON DES (N=98) (N=101) Number of Reports Cardiovascular System Congestive heart failure 1 5 ECG changes/ischemia 19 22 High blood pressure 8 5 Murmur 3 8 Peripheral edema 12 30 Phlebitis/thrombosis 2 10 Gastrointestinal System Anorexia 6 5 Constipation 7 9 Nausea/vomiting 5 17 Endocrine System Decreased testicular size 7 11 Gynecomastia/breast tenderness or pain 7 63 Hot flashes 55 12 Impotence 4 12 Hemic and Lymphatic System Anemia 5 5 Musculoskeletal System Bone pain 5 2 Myalgia 3 9 Central/Peripheral Nervous System Dizziness/lightheadedness 5 7 General pain 13 13 Headache 7 4 Insomnia/sleep disorders 7 5 Respiratory System Dyspnea 2 8 Sinus congestion 5 6 Integumentary System Dermatitis 5 8 Urogenital System Frequency/urgency 6 8 Hematuria 6 4 Urinary tract infection 3 7 Miscellaneous Asthenia 10 10 * Physiologic effect of decreased testosterone. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON. Cardiovascular System—Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli; Gastrointestinal System—Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps; Endocrine System—Libido decrease, Thyroid enlargement; Musculoskeletal System—Joint pain; Central/Peripheral Nervous System—Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders; Respiratory System—Cough, Pleural rub, Pneumonia, Pulmonary fibrosis; Integumentary System—Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System— Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous—Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone). In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving LUPRON. Cardiovascular System—Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal System—Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema; Endocrine System—Libido increase, Thyroid nodule; Musculoskeletal System—Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tenderness, Pelvic fibrosis, Spasms/cramps; Central/Peripheral Nervous System—Auditory hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of smell, Motor deficiency; Respiratory System—Chest tightness, Decreased breathing sounds, Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat, Wheezing/bronchitis; Integumentary System—Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles, Spiders; Urogenital System— Blisters on penis, Inguinal hernia, Penile swelling, Post void residual, Prostatic pain, Pyuria; Miscellaneous—Abdominal distention, Facial swelling/edema, Feet burning, Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow, Weakness. Postmarketing During postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Myocardial infarction; Endocrine System - Diabetes; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin- releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON INJECTION package inserts for other events reported in the same and different patient populations. OVERDOSAGE In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials with leuprolide acetate doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid. Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0300-3612-28 and six-vial carton, NDC 0300-3612-24. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. U.S. Patent Nos. 4,005,063 and 4,005,194. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. INFORMATION FOR PATIENTS Be sure to consult your physician with any questions you may have or for information about LUPRON INJECTION (leuprolide acetate) and its use. WHAT IS LUPRON? LUPRON INJECTION (leuprolide acetate) is chemically similar to gonadotropin releasing hormone (GnRH or LH-RH) a hormone which occurs naturally in your body. Normally, your body releases small amounts of LH-RH and this leads to events which stimulate the production of sex hormones. However, when you inject LUPRON INJECTION (leuprolide acetate), the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. LUPRON must be injected because, like insulin which is injected by diabetics, LUPRON is inactive when taken by mouth. If you were to discontinue the drug for any reason, your body would begin making testosterone again. DIRECTIONS FOR USING LUPRON 1. Wash hands thoroughly with soap and water. 2. If using a new bottle for the first time, flip off the plastic cover to expose the grey rubber stopper. Wipe metal ring and rubber stopper with an alcohol wipe each time you use LUPRON. Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT. Exchange it at your pharmacy for another container. 3. Remove outer wrapping from one syringe. Pull plunger back until the tip of the plunger is at the 0.2 mL or 20 unit mark. 4. Take cover off needle. Push the needle through the center of the rubber stopper on the LUPRON bottle. 5. Push the plunger all the way in to inject air into the bottle. 6. Keep the needle in the bottle and turn the bottle upside down. Check to make sure the tip of the needle is in the liquid. Slowly pull back on the plunger, until the syringe fills to the 0.2 mL or 20 unit mark. 7. Toward the end of a two-week period, the amount of LUPRON left in the bottle will be small. Take special care to hold the bottle straight and to keep the needle tip in liquid while pulling back on the plunger. 8. Keeping the needle in the bottle and the bottle upside down, check for air bubbles in the syringe. If you see any, push the plunger slowly in to push the air bubble back into the bottle. Keep the tip of the needle in the liquid and pull the plunger back again to fill to the 0.2 mL or 20 unit mark. 9. Do this again if necessary to eliminate air bubbles. 10. To protect your skin, inject each daily dose at a different body spot. 11. Choose an injection spot. Cleanse the injection spot with another alcohol wipe. 12. Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as you were instructed. 13. Holding the syringe as you would a pencil, thrust the needle all the way into the skin at a 90° angle. Push the plunger to administer the injection. 14. Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle at the same angle it was inserted. 15. Use the disposable syringe only once and dispose of it properly as you were instructed. Needles thrown into a garbage bag could accidentally stick someone. NEVER LEAVE SYRINGES, NEEDLES OR DRUGS WHERE CHILDREN CAN REACH THEM. SOME SPECIAL ADVICE • You may experience hot flashes when using LUPRON INJECTION (leuprolide acetate). During the first few weeks of treatment you may experience increased bone pain, increased difficulty in urinating, and less commonly but most importantly, you may experience the onset or aggravation of nerve symptoms. In any of these events, discuss the symptoms with your doctor. Like other treatment options, LUPRON may cause impotence. Notify your doctor if you develop new or worsened symptoms after beginning LUPRON treatment. • You may experience some irritation at the injection site, such as burning, itching or swelling. These reactions are usually mild and go away. If they do not, tell your doctor. • If you have experienced an allergic reaction to other drugs like LUPRON, you should not use this drug. • Do not stop taking your injections because you feel better. You need an injection every day to make sure LUPRON keeps working for you. • If you need to use an alternate to the syringe supplied with LUPRON, low-dose insulin syringes should be utilized. • When the drug level gets low, take special care to hold the bottle straight up and down and to keep the needle tip in liquid while pulling back on the plunger. • Do not try to get every last drop out of the bottle. This will increase the possibility of drawing air into the syringe and getting an incomplete dose. Some extra drug has been provided so that you can withdraw the recommended number of doses. • Tell your pharmacist when you will need LUPRON so it will be at the pharmacy when you need it. • Store below 77°F (25°C). Do not store near a radiator or other very warm place. Do not freeze. Protect from light; store vial in carton until use. • Do not leave your drug or hypodermic syringes where anyone can pick them up. • Keep this and all other medications out of reach of children. Manufactured for Abbott Laboratories North Chicago, IL 60064, U.S.A. ® – Registered (No. 3612) December, 2008 © 2008 Abbott Laboratories For Pediatric Use LUPRON® INJECTION (leuprolide acetate) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L prolinamide acetate (salt) with the following structural formula: Structural Formula LUPRON INJECTION is a sterile, aqueous solution intended for daily subcutaneous injection. It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Pharmacokinetics A pharmacokinetic study of leuprolide acetate in children has not been performed. Absorption In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate. The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population. 1. Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal plates will not close prematurely. 2. Organ Growth. Reproductive organs will return to a prepubertal state. 3. Menses. Menses, if present, will cease. INDICATIONS AND USAGE LUPRON INJECTION is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria: 1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males. 2. Clinical diagnosis should be confirmed prior to initiation of therapy: • Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be understood. • Bone age advanced 1 year beyond the chronological age. 3. Baseline evaluation should also include: • Height and weight measurements. • Sex steroid levels. • Adrenal steroid level to exclude congenital adrenal hyperplasia. • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor. • Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor. • Computerized tomography of the head to rule out intracranial tumor. CONTRAINDICATIONS 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. (See PRECAUTIONS, Pregnancy, Teratogenic Effects section.) The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed (see CLINICAL PHARMACOLOGY section). Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature. PRECAUTIONS Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON INJECTION, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Information for Parents Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the importance of continuous therapy. Adherence to daily drug administration schedules must be accepted if therapy is to be successful. Irregular dosing could restart the maturation process. • During the first 2 months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the physician. • Any irritation at the injection site should be reported to the physician immediately. If the child has experienced an allergic reaction to other drugs like LUPRON, this drug should not be used. • Report any unusual signs or symptoms to the physician, like continued pubertal changes, substantial mood swings or behavioral changes. Laboratory Tests Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6-12 months. Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see WARNINGS section). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses of 0.6 to 4 mg/kg (>100 times the clinical doses of 7.5 to 15 mg/month based on body surface area). There was a significant but not dose-related increase of pancreatic islet- cell adenomas in females and of testes interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at daily dose as high as 60 mg/kg (>5000 times the clinical doses based on body surface area). Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS section) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Geriatric Use See labeling for LUPRON INJECTION for the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials: Potential exacerbation of signs and symptoms during the first few weeks of treatment (see PRECAUTIONS section) is a concern in patients with rapidly advancing central precocious puberty. In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions considered not drug related are excluded. Number of Patients N = 395 (Percent) Body as a Whole General Pain 7 (2) Integumentary System Acne/Seborrhea 7 (2) Injection Site Reactions Including Abscess 21 (5) Rash Including Erythema Multiforme 8 (2) Urogenital System Vaginitis/Bleeding/Discharge 7 (2) In those same studies, the following adverse reactions were reported in less than 2% of the patients. Body as a Whole –Body Odor, Fever, Headache Infection; Cardiovascular System –Syncope, Vasodilation; Digestive System –Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System - Accelerated Sexual Maturity; Metabolic and Nutritional Disorders – Peripheral Edema, Weight Gain; Nervous System – Nervousness, Personality Disorder, Somnolence, Emotional Lability; Respiratory System – Epistaxis; Integumentary System Alopecia, Skin Striae; Urogenital System - Cervix Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence. Postmarketing During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Peripheral neuropathy, Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System –Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders; Urogenital System – Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. The effects on bone density in children are unknown. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin- releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON INJECTION and LUPRON DEPOT package inserts for adverse events reported in other patient populations. OVERDOSAGE In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials using leuprolide acetate in adult patients, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON INJECTION can be administered by a patient/parent or health care professional. The dose of LUPRON INJECTION must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio. After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters. The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy. As with other drugs administered by injection, the injection site should be varied periodically. Discontinuation of LUPRON INJECTION should be considered before age 11 for females and age 12 for males. The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose will be considered the maintenance dose. Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: • 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0300-3612 28. • Six-vial carton, NDC 0300-3612-24. • Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. • Use the syringes supplied with LUPRON INJECTION. Insulin syringes may be substituted for use with LUPRON INJECTION. U.S. Patent Nos. 4,005,063; 4,005,194. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. Manufactured for Abbott Laboratories North Chicago, IL 60064, U.S.A. ® – Registered (No. 3612) ADMINISTERING THE INJECTION Read this booklet before injecting the medication. Read the complete instructions for injection. Abbott Laboratories North Chicago, IL 60064, U.S.A. (No. 3612) December, 2008 © 2008 Abbott Laboratories Provided as an educational service by Abbott Laboratories Abbott Laboratories North Chicago, IL 60064, U.S.A. ADMINISTERING THE INJECTION 1. Wash hands thoroughly. Usage Illustration 2. Check the liquid in the container. It should look clear. DO NOT USE if it is not clear or if it has particles in it. If using a new bottle, flip off the plastic cover to expose the grey rubber stopper. Use an alcohol swab to cleanse the metal ring and rubber stopper on medication bottle every day, just before you use it. 3. Remove outer wrapping from one syringe. Usage Illustration 4. Pull the syringe plunger back until its tip is at the proper mark. Usage Illustration 5. Uncover needle. Do not touch the needle. Usage Illustration 6. Place the bottle on a clean, flat surface and push the needle through the center of the rubber stopper on the bottle. Push the plunger all the way in to inject air into the bottle. Usage Illustration 7. Keep the needle in the bottle. Lift the bottle and turn it straight upside down. Check to see that the needle tip is in the liquid. Usage Illustration 8. With the needle tip in the liquid, slowly pull back the plunger until syringe fills to the proper mark. If any bubbles appear in the syringe, remove them by pushing the plunger up slowly. With the needle tip still in the liquid, pull the plunger until it is once more at the proper mark. Usage Illustration 9. Choose a different injection site each day. Cleanse the injection site with a new alcohol swab. Hold the skin the way you were instructed. Slide the needle quickly all the way through the skin, into the subcutaneous tissue, at a 90° angle. Usage Illustration 10. Push the plunger to inject the medication. Withdraw the needle at the same angle it was inserted (90°). Wipe the skin with an alcohol swab. Dispose of the syringe and alcohol swabs as you were instructed. Remember: use the disposable syringe only once. Usage Illustration 11. Package Insert for NDA 019732/S-031/ S-035/S-036 LUPRON DEPOT 7.5 mg Package Insert labeling note Lupron Depot (Ieuprolide acetate) Injection, Powder, Lyophilized, For Suspension (Abbott Laboratories) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo- L-proly l- L-histidy l- L-tryptophy l- L-sery l- L-tyrosyl- D- leucy l- L- leucyl- L-arginyl- N -ethy l- L- prolinamide acetate (salt) with the following structural formula: Structural Formula ( LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized micro spheres which, when mixed with diluent, becomes a suspension intended as a monthly intramuscular injection. The front chamber of LUPRON DEPOT 7.5 mg prefilled dual-chamber syringe contains leuprolide acetate (7.5 mg), purified gelatin (1.3 mg), DL-lactic and glycolic acids copolymer (66.2 mg), and D- mannitol (13.2 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D- mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH. During the manufacture of LUPRON DEPOT 7.5 mg, acetic acid is lost, leaving the peptide. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These decreases occur within two to four weeks after ( LUPRON DEPOT 7.5 mg Package Insert Page 2 of9 initiation of treatment. Castrate levels of testosterone in prostatic cancer patients have been demonstrated for up to 10 years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption: Following a single injection of LUPRON DEPOT 7.5 mg to patients, mean plasma leuprolide concentration was almost 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT 7.5 mg administration, but testosterone levels appear to be maintained at castrate levels. Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism: In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment modeL. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion: Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% ofthe dose was recovered as parent and M-I metabolite in the urine. Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined. Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In an open-label, non-comparative, multicenter clinical study of LUPRON DEPOT 7.5 mg, 56 patients with stage Di prostatic adenocarcinoma and no prior systemic treatment were enrolled. The objectives were to determine if a 7.5 mg depot formulation of leu pro Ii de injected once every 4 weeks would reduce and maintain seru testosterone to castrate range (~50 ng/dL), to evaluate objective clinical response, and to assess the safety ofthe formulation. During the initial 24 weeks, serum testosterone was measured weekly, biweekly, or every four weeks and objective tumor response assessments were performed at Weeks 12 and 24. Once the patient completed the initial 24-week treatment phase, treatment continued at the investigator's discretion. Data from the initial 24-week treatment phase are summarized in this section. In the majority of patients, serum testosterone increased by 50% or more above baseline during the first week of treatment. Serum testosterone suppressed to the castrate range within 30 days of the initial depot patients for whom testosterone suppression was achieved (2 patients withdrew prior to onset of suppression) and within 66 days in all 54 patients. Mean serum testosterone suppressed to injection in 94% (51/54) of LUPRON DEPOT 7.5 mg Package Insert Page 30f9 castrate level by Week 3. The median dosing interval between injections was 28 days. One escape from suppression (2 consecutive testosterone values greater than 50 ng/dL after achieving castrate level) was noted at Week 18, associated with a substantial dosing delay. In this patient, serum testosterone returned to the castrate range at the next monthly measurement. Serum testosterone was minimally above the castrate range on a single occasion for 4 other patients. No clinical significance was attributed to these rises in testosterone. Lupron Depot.7.5 mg Mean Serum Testosterone Concentrations .. 7úO .. :E. 600 Olc -;- 500 c ~ 400 û)o 30U ti 50 ngldL =c"s;ialt level ~ QOO E 2 înj.#2 nj.#3 In¡.#4 I~i' I "Ii d5 ! ! ! o o .2 4 6 8 10 12 14 16 1B 20 22 24 Weeks Secondary efficacy endpoints evaluated included objective tumor response, assessed by clinical tumor burden (complete response, partial response, objectively stable, and progression), as well as changes in local disease status, assessed by digital rectal examination, and changes in prostatic acid phosphatase (PAP). These evaluations were performed at Weeks 12 and 24. The objective tumor response analysis showed a "no progression" (ie. complete or parial response, or stable disease) in 77% (40/52) of evaluations of patients at Week 12, and in 84% (42/50) of patients at Week 24. Local disease improved or remained stable patients elevated at Week 24. PAP in all (42) patients evaluated at Week 12 and in 98% (41/42) of patients with elevated baseline PAP. Periodic monitoring of seru testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. normalized or decreased at Week 12 and/or 24 in the majority of INDICATIONS AND USAGE LUPRON DEPOT 7.5 mg is indicated in the palliative treatment of advanced prostatic cancer. CONTRAINDICATIONS the excipients in LUPRONDEPOT. Reports of anaphylactic reactions to GnR agonist analogs have been reported in the medical literature. 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of LUPRON DEPOT 7.5 mg Package Insert Page 4 of9 LUPRON DEPOT are contraindicated in women who are or may become pregnant while receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after 2. All formulations of LUPRON DEPOT throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur. If this drug is administered during pregnancy or if the patient administration of LUPRON DEPOT, the patient should be apprised of the potential hazard to the fetus. becomes pregnant while taking any formulation of WARNINGS Initially, LUPRON DEPOT, like other LH-RH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first week of treatment. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated first few weeks of LUPRON DEPOT treatment. A small number of may contribute to cases of ureteral obstruction and spinal cord compression have been observed, which paralysis with or without fatal complications. For patients at risk, initiation oftherapy with daily LUPRONI (leuprolide acetate) Injection (see DOSAGE AND ADMINISTRATION section in the LUPRON Injection labeling) for the first two weeks to facilitate withdrawal of treatment may be considered. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted. PRECAUTIONS Information for Patients: An information pamphlet for patients is included with the product. General: Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be therapy (see WARNINGS section). Laboratory Tests: Response to LUPRON DEPOT 7.5 mg should be monitored by measuring serum closely observed during the first few weeks of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. Castrate levels were reached within two to four weeks and once achieved were maintained for the duration of treatment in all 54 patients. Minimal and transient increases to above the castrate level occurred in eight patients (see CLINICAL STUDIES section). levels of testosterone as well as prostate-specific antigen. In the majority of Drug Interactions: (See Pharmacokinetics.) LUPRON DEPOT in therapeutic doses results in suppression ofthe pituitary-gonadal system. Normal function is usually restored within three months DruglLaboratory Test Interactions: Administration of after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUPRON DEPOT, diagnostic tests of pituitar gonadotropic and gonadal functions conducted during LUPRON DEPOT may be affected. Carcinogenesis, Mutagenesis, Impairment of Fertilty: Two-year carcinogenicity studies were treatment and for up to three months after discontinuation of conducted in rats and mice. In rats, a dose-related increase of benign pituitar hyperplasia and benign pituitar adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell LUPRON DEPOT 7.5 mg Package Insert Page 50f9 adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 1 a mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potentiaL. Clinical and pharmacologic studies in adults (~ 18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. Pregnancy Category X. See CONTRAINDICATIONS section. Pediatric Use: See LUPRON DEPOT-PED(j (leuprolide acetate for depot suspension) labeling for the the monthly formulation in children with central precocious puberty. safety and effectiveness of the subjects studied Geriatric Use: In the clinical trials for LUPRON DEPOT, the majority (68%) of were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON DEPOT in this population. ADVERSE REACTIONS Clinical Trials In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to the lower limbs or worsening of urinary symptoms (see WARNINGS section). In a clinical trial of LUPRON DEPOT 7.5 mg, the following adverse reactions were reported in 5% or more ofthe patients during the initial 24-week treatment period regardless of causality. neurological problems such as temporary weakness and/or paresthesia of LUPRON DEPOT 7.5 mg Package Insert Page 60f9 LUPRON DEPOT 7.5 mg (N=56) N (%) Body as a Whole General pain 13 (23.2) Infection 3 (5.4) Cardiovascular System Hot flashes/sweats* 32 (57.1) Digestive System GI disorders 8 (14.3) Metabolic and Nutritional Disorders Edema Nervous System Libido decreased* Respiratory System Respiratory disorder Urogenital System Urinary disorder Impotence* Testicular atrophy* 8 (14.3) 3 (5.4) 6 (10.7) 7 (12.5) 3 (5.4) 3 (5.4) Due to the expected physiologic effect of decreased testosterone levels. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT 7.5 mg. Body as a Whole - Asthenia, Cellulitis, Fever, Headache, Injection site reaction, Neoplasm; Cardiovascular System - Angina, Congestive hear failure; Digestive System - Anorexia, Dysphagia, Eructation, Peptic ulcer; Hemic and Lymphatic System - Ecchymosis; Musculoskeletal System - Myalgia; Central/Peripheral Nervous System - Agitation, Convulsion, Insomnia/sleep disorders, Neuromuscular disorders; Respiratory System - Emphysema, Hemoptysis, Lung edema, Sputum increased; Skin and Appendages - Hair disorder, Skin reaction; Urogenital System - Balanitis, Breast enlargement, Urinary tract infection. Laboratory: Abnormalities of certain parameters were observed, but their relationship to drug treatment are diffcult to assess in this population. The following were recorded in ~5% of patients at final visit: Decreased albumin, decreased hemoglobin/hematocrit, decreased prostatic acid phosphatase, decreased total protein, decreased urine specific gravity, hyperglycemia, hyperuricemia, increased BUN, increased creatinine, increased liver function tests (AST, LDH), increased phosphorus, increased platelets, increased prostatic acid phosphatase, increased total cholesterol, increased urine specific gravity, leukopenia. Postmarketing During postmarketing surveilance, which includes other dosage forms and other patient populations, the following adverse events were reported. LUPRON DEPOT 7.5 mg Package Insert Page 70f9 Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, uricaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg, joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System - Hypotension, Myocardial infarction, Pulmonary embolism; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis; Endocrine System - Diabetes; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clini.cal trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men wil have effects on bone density. Pituitary apoplexy: During post-marketing surveilance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority ofthese cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in women and pediatric populations. OVERDOSAGE In clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician. The recommended dose of LUPRON DEPOT is 7.5 mg, incorporated in a depot formulation. The lyophilized microspheres are to be reconstituted and administered monthly as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read andfollow the following instructions: 1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normaL. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. 3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the bareL. 4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a uniform suspension. The suspension wil appear milky. If the powder adheres to the stopper or LUPRON DEPOT 7.5 mg Package Insert Page 8of9 caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. 5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is 7. Inject the entire contents of the syringe intramuscularly at the time of accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™ safety device. AFTER INJECTION 8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt. Since the product does not contain a preservative, the suspension should be discarded if not used immediately. As with other drugs administered by injection, the injection site should be varied periodically. HOW SUPPLIED Each LUPRON DEPOT 7.5 mg kit (NDC 0074-3642-03) contains: . one prefilled dual-chamber syringe, . one plunger, . two alcohol swabs, . instructions for how to mix and administer, . an information pamphlet for patients, and . a complete prescribing information enclosure. The prefilled dual-chamber syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid/glycolic acid copolymer. When mixed with 1 mL of accompanying diluent, LUPRON DEPOT 7.5 mg is administered as a single monthly intramuscular injection. Store at 25°C (77°F); excursions permitted to IS-30°C (59-86°F) (See USP Controlled Room Temperature). REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. healthcare settings. 2004. U.S. Deparment of 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://ww.osha.gov/dts/osta/otm/otm vi/otm vi 2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63: 1172- 1193. LUPRON DEPOT 7.5 mg Package Insert Page 90f9 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721; 4,849,228; 4,917,893; 5,330,767; 5,476,663; 5,575,987; 5,631,020; 5,631,021; 5,716,640; 5,823,997; 5,980,488; and 6,036,976. Other patents pending. Manufactured for Abbott Laboratories North Chicago, IL 60064 By Takeda Pharaceutical Company Limited Osaka, lAP AN 540-8645 ™ -Trademark ~-Registered Trademark (No. 3642) Package Insert for NDA 020517/S-024/ S-028/S-029 3 Month formulation LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 1 of 9 Lupron Depot (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For Suspension [Abbott Laboratories] 3-MONTH FORMULATION Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: Structural Formula LUPRON DEPOT–3 Month 22.5 mg is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY THREE MONTHS (84 days). The front chamber of LUPRON DEPOT–3 Month 22.5 mg prefilled dual-chamber syringe contains leuprolide acetate (22.5 mg), polylactic acid (198.6 mg) and D-mannitol (38.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. During the manufacture of LUPRON DEPOT–3 Month 22.5 mg, acetic acid is lost, leaving the peptide. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 2 of 9 levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for more than five years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption Following a single injection of the three month formulation of LUPRON DEPOT– 3 Month 22.5 mg in patients, mean peak plasma leuprolide concentration of 48.9 ng/mL was observed at 4 hours and then declined to 0.67 ng/mL at 12 weeks. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Detectable levels of leuprolide were present at all measurement points in all patients. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the monthly formulation. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT® 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined. CLINICAL STUDIES In clinical studies, serum testosterone was suppressed to castrate within 30 days in 87 of 92 (95%) patients and within an additional two weeks in three patients. Two patients did not suppress for 15 and 28 weeks, respectively. Suppression was maintained in all of these patients with the exception of transient minimal testosterone elevations in one of them, and in another an increase in serum testosterone to above the castrate range was recorded during the 12 hour observation period after a subsequent injection. This represents stimulation of gonadotropin secretion. LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 3 of 9 Graph An 85% rate of “no progression” was achieved during the initial 24 weeks of treatment. A decrease from baseline in serum PSA of ≥90% was reported in 71% of the patients and a change to within the normal range (≤3.99 ng/mL) in 63% of the patients. Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. INDICATIONS AND USAGE LUPRON DEPOT–3 Month 22.5 mg is indicated in the palliative treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient. In clinical trials, the safety and efficacy of LUPRON DEPOT–3 Month 22.5 mg were similar to that of the original daily subcutaneous injection and the monthly depot formulation. CONTRAINDICATIONS Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. LUPRON DEPOT is contraindicated in women who are or may become pregnant while receiving the drug. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 of the human dose) to rabbits, the monthly formulation of LUPRON DEPOT produced a LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 4 of 9 dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of LUPRON DEPOT in rabbits and with the highest dose in rats. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. WARNINGS Isolated cases of worsening of signs and symptoms during the first weeks of treatment have been reported with LH-RH analogs. Worsening of symptoms may contribute to paralysis with or without fatal complications. For patients at risk, the physician may consider initiating therapy with daily LUPRON® (leuprolide acetate) Injection for the first two weeks to facilitate withdrawal of treatment if that is considered necessary. PRECAUTIONS Information for Patients An information pamphlet for patients is included with the product. General Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS section). Laboratory Tests Response to LUPRON DEPOT–3 Month 22.5 mg should be monitored by measuring serum levels of testosterone, as well as prostate-specific antigen and prostatic acid phosphatase. In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. Castrate levels were reached within two to four weeks and once achieved were maintained for as long as the patients received their injections. Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. Drug/Laboratory Test Interactions Administration of LUPRON DEPOT 3.75 mg in women results in suppression of the pituitary-gonadal system. Normal function is usually restored within one to three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to three months after discontinuation of LUPRON DEPOT 3.75 mg therapy may be misleading. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet- cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 5 of 9 Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. Pregnancy, Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS section). Pediatric Use See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness of the monthly formulation in children with central precocious puberty. Geriatric Use In the clinical trials for LUPRON DEPOT – 3 Month 22.5 mg, the majority (80%) of the subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON DEPOT in this population. ADVERSE REACTIONS Clinical Trials In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms (see WARNINGS section). In two clinical trials of LUPRON DEPOT–3 Month 22.5 mg, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician in 5% or more of the patients receiving the drug. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded. LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 6 of 9 Body As A Whole Asthenia General Pain Headache Injection Site Reaction Cardiovascular System Hot flashes/Sweats Digestive System GI Disorders Musculoskeletal System Joint Disorders Central/Peripheral Nervous System Dizziness/Vertigo Insomnia/Sleep Disorders Neuromuscular Disorders Respiratory System Respiratory Disorders Skin and Appendages Skin Reaction Urogenital System Testicular Atrophy* Urinary Disorders LUPRON DEPOT-3 Month 22.5 mg N=94 (%) 7 25 6 13 (7.4) (26.6) (6.4) (13.8) 55 (58.5) 15 (16.0) 11 (11.7) 6 8 9 (6.4) (8.5) (9.6) 6 (6.4) 8 (8.5) 19 14 (20.2) (14.9) Physiologic effect of decreased testosterone. In these same studies, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT–3 Month 22.5 mg. Body As A Whole - Enlarged abdomen, Fever; Cardiovascular System - Arrhythmia, Bradycardia, Heart failure, Hypertension, Hypotension, Varicose vein; Digestive System - Anorexia, Duodenal ulcer, Increased appetite, Thirst/dry mouth; Hemic and Lymphatic System - Anemia, Lymphedema; Metabolic and Nutritional Disorders - Dehydration, Edema; Central/Peripheral Nervous System - Anxiety, Convulsion, Delusions, Depression, Hypesthesia, Libido decreased, Nervousness, Paresthesia; Respiratory System - Epistaxis, Pharyngitis, Pleural effusion, Pneumonia; Special Senses - Abnormal vision, Amblyopia, Dry eyes, Tinnitus; Urogenital System - Gynecomastia, Impotence, Penis disorders, Testis disorders. Laboratory: Abnormalities of certain parameters were observed, but are difficult to assess in this population. The following were recorded in ≥5% of patients: Increased BUN, Hyperglycemia, Hyperlipidemia (total cholesterol, LDL-cholesterol, triglycerides), Hyperphosphatemia, Abnormal liver function tests, Increased PT, Increased PTT. Additional laboratory abnormalities reported were: Decreased platelets, Decreased potassium and Increased WBC. LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 7 of 9 Postmarketing During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg, joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Myocardial infarction, Pulmonary embolism; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis; Endocrine System – Diabetes; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in women and pediatric populations. OVERDOSAGE In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician. The recommended dose of LUPRON DEPOT–3 Month 22.5 mg to be administered is one injection every three months (84 days). Due to different release characteristics, a fractional dose of this 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given. LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 8 of 9 Incorporated in a depot formulation, the lyophilized microspheres are to be reconstituted and administered every three months as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions: 1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. 3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. 4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. 5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. 7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™ safety device. AFTER INJECTION 8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt. Since the product does not contain a preservative, the suspension should be discarded if not used immediately. As with other drugs administered by injection, the injection site should be varied periodically. HOW SUPPLIED Each LUPRON DEPOT- 3 Month 22.5 mg kit (NDC 0074-3346-03) contains: • One prefilled dual-chamber syringe, • One plunger, • Two alcohol swabs, • Instructions for how to mix and administer, • An information pamphlet for patients, and • A complete prescribing information enclosure. The prefilled dual-chamber syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer. When mixed with 1.5 mL of accompanying diluent, LUPRON DEPOT – 3 Month 22.5 mg is administered as a single monthly intramuscular injection EVERY THREE MONTHS (84 days). LUPRON DEPOT - 3 Month 22.5 mg Package Insert Page 9 of 9 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature] REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. U.S. Patent Nos. 4,728,721; 4,849,228; 5,330,767; 5,476,663; 5,480,656; 5,575,987; 5,631,020; 5,631,021; 5,643,607; 5,716,640; 5,814,342; 5,823,997; 5,980,488 and 6,036,976. Other patents pending. Manufactured for Abbott Laboratories North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, JAPAN 540-8645 TM-Trademark ® – Registered trademark Package Insert for NDA 020517/S-024/ S-028/S-029 4 Month formulation Lupron Depot (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For Suspension [Abbott Laboratories] 4-MONTH FORMULATION Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: Structural Formula LUPRON DEPOT-4 Month 30 mg is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY FOUR MONTHS (16 weeks). The front chamber of LUPRON DEPOT-4 Month 30 mg prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH. During the manufacture of LUPRON DEPOT-4 Month 30 mg, acetic acid is lost, leaving the peptide. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In premenopausal females, estrogens are reduced to postmenopausal levels. These decreases occur within two to four weeks after initiation of treatment. Castrate levels of testosterone in prostatic cancer patients have been demonstrated for more than five years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption: Following a single injection of LUPRON DEPOT-4 Month 30 mg in sixteen orchiectomized prostate cancer patients, mean plasma leuprolide concentration of 59.3 ng/mL was observed at 4 hours and the mean concentration then declined to 0.30 ng/mL at 16 weeks. The mean plasma concentration of leuprolide from weeks 3.5 to 16 was 0.44 ± 0.20 ng/mL (range: 0.20-1.06). Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the fourth week after dosing, providing steady plasma concentrations throughout the 16-week dosing interval. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. The initial burst, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the other depot formulations. Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism: In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion: Following administration of LUPRON DEPOT® 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined. Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In an open-label, noncomparative, multicenter clinical study of LUPRON DEPOT-4 Month 30 mg, 49 patients with stage D2 prostatic adenocarcinoma (with no prior treatment) were enrolled. The objectives were to determine whether a 30 mg depot formulation of leuprolide injected once every 16 weeks would reduce and maintain serum testosterone levels at castrate levels (≤ 50 ng/dL), and to assess the safety of the formulation. The study was divided into an initial 32-week treatment phase and a long- term treatment phase. Serum testosterone levels were determined biweekly or weekly during the first 32 weeks of treatment. Once the patient completed the initial 32-week treatment period, treatment continued at the investigator’s discretion with serum testosterone levels being done every 4 months prior to the injection. In the majority of patients, testosterone levels increased 50% or more above the baseline during the first week of treatment. Mean serum testosterone subsequently suppressed to castrate levels within 30 days of the first injection in 94% of patients and within 43 days in all 49 patients during the initial 32 week treatment period. The median dosing interval between injections was 112 days. One escape from suppression (two consecutive testosterone values greater than 50 ng/dL after castrate levels achieved) was noted at Week 16. In this patient, serum testosterone increased to above the castrate range following the second depot injection (Week 16) but returned to the castrate level by Week 18. No adverse events were associated with this rise in serum testosterone. A second patient had a rise in testosterone at Week 17, then returned to the castrate level by Week 18 and remained there through Week 32. In the long-term treatment phase two patients experienced testosterone elevations, both at Week 48. Testosterone for one patient returned to the castrate range at Week 52, and one patient discontinued the study at Week 48 due to disease progression. Secondary efficacy endpoints evaluated in the study were the objective tumor response as assessed by clinical evaluations of tumor burden (complete response, partial response, objectively stable and progression) and evaluations of changes in prostatic involvement and prostate-specific antigen (PSA). These evaluations were performed at Weeks 16 and 32 of the treatment phase. The long-term treatment phase monitored PSA at each visit (every 16 weeks). The objective tumor response analysis showed “no progression” (i.e. complete or partial response, or stable disease) in 86% (37/43) of patients at Week 16, and in 77% (37/48) of patients at Week 32. Local disease improved or remained stable in all patients evaluated at Week 16 and/or 32. For patients with elevated baseline PSA, 50% (23/46) had a normal PSA (less than 4.0 ng/mL) at Week 16, and 51% (19/37) had a normal PSA at Week 32. Periodic monitoring of serum testosterone and PSA levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. Using historical comparisons, the safety and efficacy of LUPRON DEPOT-4 Month 30 mg appear similar to the other LUPRON DEPOT formulations. Graph INDICATIONS AND USAGE LUPRON DEPOT-4 Month 30 mg is indicated in the palliative treatment of advanced prostatic cancer. CONTRAINDICATIONS 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2. This formulation is not indicated for use in women. (See LUPRON DEPOT 3.75 mg and LUPRON DEPOT®–3 Month 11.25 mg package inserts.) 3. All formulations of LUPRON DEPOT are contraindicated in women who are or may become pregnant while receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of LUPRON DEPOT throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur. If this drug is used during pregnancy, or if the patient becomes pregnant while taking any formulation of LUPRON DEPOT, the patient should be apprised of the potential hazard to the fetus. WARNINGS Initially, LUPRON DEPOT, like other LH-RH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first week of treatment. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LUPRON DEPOT treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. For patients at risk, initiation of therapy with daily LUPRON® (leuprolide acetate) Injection (See DOSAGE AND ADMINISTRATION section in the LUPRON Injection labeling.) for the first two weeks to facilitate withdrawal of treatment may be considered. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted. PRECAUTIONS Information for Patients: An information pamphlet for patients is included with the product. General Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. (See WARNINGS section.) Laboratory Tests: Response to LUPRON DEPOT-4 Month 30 mg should be monitored by measuring serum levels of testosterone, as well as prostate-specific antigen. In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. Castrate levels were reached within two to four weeks and once achieved were maintained in most (45/49) patients for as long as the patients received their injections. (See CLINICAL STUDIES and ADVERSE REACTIONS.) Drug Interactions: See CLINICAL PHARMACOLOGY, Pharmacokinetics. Drug/Laboratory Test Interactions: Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUPRON DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of LUPRON DEPOT may be affected. Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet- cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. Pregnancy, Teratogenic Effects: Pregnancy Category X. (See CONTRAINDICATIONS section.) Pediatric Use: Safety and effectiveness of LUPRON DEPOT-4 Month 30 mg have not been established in pediatric patients. See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness of the monthly formulation in children with central precocious puberty. Geriatric Use: In the clinical trials for LUPRON DEPOT – 4 Month 30 mg, the majority (79%) of the subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON DEPOT in this population. ADVERSE REACTIONS Clinical Trials The 4-month formulation of LUPRON DEPOT 30 mg was utilized in clinical trials that studied the drug in 49 nonorchiectomized prostate cancer patients for 32 weeks or longer and in 24 orchiectomized prostate cancer patients for 20 weeks. In the majority of nonorchiectomized patients, testosterone levels increased 50% or more above baseline during the first week of treatment with LUPRON DEPOT, declining thereafter to baseline levels or below by the end of the second week of treatment. Therefore, potential exacerbations of signs and symptoms during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms. (See WARNINGS section.) In the above described clinical trials, the following adverse reactions were reported in ≥ 5% of the patients during the treatment period regardless of causality. Adverse Events Reported in ≥ 5% of Patients Regardless of Causality LUPRON DEPOT-4 Month 30 mg Body As a Whole Asthenia Flu Syndrome General Pain Headache Injection Site Reaction Cardiovascular System Hot flashes/Sweats Digestive System GI Disorders Metabolic and Nutritional Disorders Dehydration Edema Musculoskeletal System Joint Disorder Myalgia Nervous System Dizziness/Vertigo Neuromuscular Disorders Paresthesia Respiratory System Respiratory Disorder Skin and Appendages Skin Reaction Urogenital System Urinary Disorders Nonorchiectomized, N = 49 Study 013 Orchiectomized, N = 24 Study 012 N (%) N (%) 6 (12.2) 1 (4.2) 6 (12.2) 0 (0.0) 16 (32.7) 1 (4.2) 5 (10.2) 1 (4.2) 4 (8.2) 9 (37.5) 23 (46.9) 2 (8.3) 5 (10.2) 3 (12.5) 4 (8.2) 0 (0.0) 4 (8.2) 5 (20.8) 8 (16.3) 1 (4.2) 4 (8.2) 0 (0.0) 3 (6.1) 2 (8.3) 3 (6.1) 1 (4.2) 4 (8.2) 1 (4.2) 4 (8.2) 1 (4.2) 6 (12.2) 0 (0.0) 5 (10.2) 4 (16.7) * Due to the expected physiologic effects of decreased testosterone levels. In these same studies, the following adverse reactions were reported in less than 5% of the patients on LUPRON DEPOT-4 Month 30 mg. Body As a Whole - Abscess, Accidental injury, Allergic reaction, Cyst, Fever, Generalized edema, Hernia, Neck pain, Neoplasm; Cardiovascular System - Atrial fibrillation, Deep thrombophlebitis, Hypertension; Digestive System - Anorexia, Eructation, Gastrointestinal hemorrhage, Gingivitis, Gum hemorrhage, Hepatomegaly, Increased appetite, Intestinal obstruction, Peridontal abscess; Hemic and Lymphatic System - Lymphadenopathy; Metabolic and Nutritional Disorders - Healing abnormal, Hypoxia, Weight loss; Musculoskeletal System - Leg cramps, Pathological fracture, Ptosis; Nervous System - Abnormal thinking, Amnesia, Confusion, Convulsion, Dementia, Depression, Insomnia/sleep disorders, Libido decreased, Neuropathy, Paralysis; Respiratory System - Asthma, Bronchitis, Hiccup, Lung disorder, Sinusitis, Voice alteration; Skin and Appendages - Herpes zoster, Melanosis; Urogenital System - Bladder carcinoma, Epididymitis, Impotence, Prostate disorder, Testicular atrophy*, Urinary incontinence, Urinary tract infection. Laboratory: Abnormalities of certain parameters were observed, but their relationship to drug treatment is difficult to assess in this population. The following were recorded in ≥ 5% of patients: Decreased bicarbonate, Decreased hemoglobin/hematocrit/RBC, Hyperlipidemia (total cholesterol, LDL-cholesterol, triglycerides), Decreased HDL-cholesterol, Eosinophilia, Increased glucose, Increased liver function tests (ALT, AST, GGTP, LDH), Increased phosphorus. Additional laboratory abnormalities were reported: Increased BUN and PT, Leukopenia, Thrombocytopenia, Uricaciduria. Postmarketing During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg, joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System - Hypotension, Myocardial infarction, Pulmonary embolism; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System – Convulsion, Peripheral neuropathy, Spinal fracture/paralysis; Endocrine System – Diabetes; Musculoskeletal System Tenosynovitis-like symptoms; Urogenital System - Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in women and pediatric populations. OVERDOSAGE In clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician. The recommended dose of LUPRON DEPOT-4 Month 30 mg to be administered is one injection EVERY FOUR MONTHS (16 weeks). Due to different release characteristics, a fractional dose of this 4-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given. Incorporated in a depot formulation, the lyophilized microspheres are to be reconstituted and administered EVERY FOUR MONTHS (16 weeks) as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions: 1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. 3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel. 4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. 5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. 7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™ safety device. AFTER INJECTION 8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt. Since the product does not contain a preservative, the suspension should be discarded if not used immediately. As with other drugs administered by injection, the injection site should be varied periodically. HOW SUPPLIED Each LUPRON DEPOT 4 Month 30 mg kit (NDC 0074-3683-03) contains: • One prefilled dual-chamber syringe, • One plunger, • Two alcohol swabs, • Instructions for how to mix and administer, • An information pamphlet for patients, and • A complete prescribing information enclosure. The prefilled dual-chamber syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer. When mixed with 1.5 mL of accompanying diluent, LUPRON DEPOT – 4 Month 30 mg is administered as a single monthly intramuscular injection EVERY FOUR MONTHS (16 weeks). Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature] REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. U.S. Patent Nos. 4,728,721; 4,849,228; 5,330,767; 5,476,663; 5,480,656; 5,575,987; 5,631,020; 5,631,021; 5,643,607; 5,716,640; 5,814,342; 5,823,997; 5,980,488; and 6,036,976. Other patents pending. Manufactured for Abbott Laboratories North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, JAPAN 540-8645 TM – Trademark ® – Registered Trademark (No. 3683)	custom-source	2025-02-12T13:45:12.040167	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019010s033,019732s031s035s036,020517s024s028s029lbl.pdf', 'application_number': 19010, 'submission_type': 'SUPPL ', 'submission_number': 33}
11,414		custom-source	2025-02-12T13:45:12.043351	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/19-012S016_Ibuprofen_prntlbl.pdf', 'application_number': 19012, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,412	structural formula Lupron (leuprolide acetate) Injection, Solution [Abbott Laboratories] Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption Bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Drug Interactions Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In a controlled study comparing LUPRON 1 mg/day given subcutaneously to DES (diethylstilbestrol), 3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The objective response to treatment was also similar for the two groups. INDICATIONS AND USAGE LUPRON INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced prostatic cancer. CONTRAINDICATIONS 1. LUPRON INJECTION is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION: Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature.1,2 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS Initially, LUPRON, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LUPRON treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON, pregnancy must be excluded (see CONTRAINDICATIONS section). Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. PRECAUTIONS Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS sections). Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Information for Patients See INFORMATION FOR PATIENTS which appears after the REFERENCE section. Laboratory Tests Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Pediatric Use Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children with central precocious puberty. Geriatric Use In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction. In a comparative trial of LUPRON INJECTION (leuprolide acetate) versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded. LUPRON DES (N=98) (N=101) Number of Reports Cardiovascular System Congestive heart failure 1 5 ECG changes/ischemia 19 22 High blood pressure 8 5 Murmur 3 8 Peripheral edema 12 30 Phlebitis/thrombosis 2 10 Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gastrointestinal System Anorexia 6 5 Constipation 7 9 Nausea/vomiting 5 17 Endocrine System Decreased testicular size 7 11 Gynecomastia/breast tenderness or pain 7 63 Hot flashes 55 12 Impotence 4 12 Hemic and Lymphatic System Anemia 5 5 Musculoskeletal System Bone pain 5 2 Myalgia 3 9 Central/Peripheral Nervous System Dizziness/lightheadedness 5 7 General pain 13 13 Headache 7 4 Insomnia/sleep disorders 7 5 Respiratory System Dyspnea 2 8 Sinus congestion 5 6 Integumentary System Dermatitis 5 8 Urogenital System Frequency/urgency 6 8 Hematuria 6 4 Urinary tract infection 3 7 Miscellaneous Asthenia 10 10 * Physiologic effect of decreased testosterone. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON. Cardiovascular System—Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli; Gastrointestinal System—Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps; Endocrine System—Libido decrease, Thyroid enlargement; Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Musculoskeletal System—Joint pain; Central/Peripheral Nervous System—Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders; Respiratory System—Cough, Pleural rub, Pneumonia, Pulmonary fibrosis; Integumentary System—Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System— Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous— Depression, Diabetes, Fatigue, Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone). In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving LUPRON. Cardiovascular System—Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal System—Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema; Endocrine System—Libido increase, Thyroid nodule; Musculoskeletal System—Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tenderness, Pelvic fibrosis, Spasms/cramps; Central/Peripheral Nervous System—Auditory hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of smell, Motor deficiency; Respiratory System—Chest tightness, Decreased breathing sounds, Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat, Wheezing/bronchitis; Integumentary System—Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles, Spiders; Urogenital System— Blisters on penis, Inguinal hernia, Penile swelling, Post void residual, Prostatic pain, Pyuria; Miscellaneous—Abdominal distention, Facial swelling/edema, Feet burning, Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow, Weakness. Postmarketing During postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Myocardial infarction; Endocrine System - Diabetes; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Convulsion, Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON INJECTION package inserts for other events reported in the same and different patient populations. OVERDOSAGE In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials with leuprolide acetate doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid. Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0074-3612-30 and six-vial carton, NDC 0074-3612-34. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. U.S. Patent Nos. 4,005,063 and 4,005,194. REFERENCES 1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct; 161(3): 455. 2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol 1991 Nov; 78: 943–946. INFORMATION FOR PATIENTS Be sure to consult your physician with any questions you may have or for information about LUPRON INJECTION (leuprolide acetate) and its use. WHAT IS LUPRON? LUPRON INJECTION (leuprolide acetate) is chemically similar to gonadotropin releasing hormone (GnRH or LH-RH) a hormone which occurs naturally in your body. Normally, your body releases small amounts of LH-RH and this leads to events which stimulate the production of sex hormones. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda However, when you inject LUPRON INJECTION (leuprolide acetate), the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. LUPRON must be injected because, like insulin which is injected by diabetics, LUPRON is inactive when taken by mouth. If you were to discontinue the drug for any reason, your body would begin making testosterone again. DIRECTIONS FOR USING LUPRON 1. Wash hands thoroughly with soap and water. 2. If using a new bottle for the first time, flip off the plastic cover to expose the grey rubber stopper. Wipe metal ring and rubber stopper with an alcohol wipe each time you use LUPRON. Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT. Exchange it at your pharmacy for another container. 3. Remove outer wrapping from one syringe. Pull plunger back until the tip of the plunger is at the 0.2 mL or 20 unit mark. 4. Take cover off needle. Push the needle through the center of the rubber stopper on the LUPRON bottle. 5. Push the plunger all the way in to inject air into the bottle. 6. Keep the needle in the bottle and turn the bottle upside down. Check to make sure the tip of the needle is in the liquid. Slowly pull back on the plunger, until the syringe fills to the 0.2 mL or 20 unit mark. 7. Toward the end of a two-week period, the amount of LUPRON left in the bottle will be small. Take special care to hold the bottle straight and to keep the needle tip in liquid while pulling back on the plunger. 8. Keeping the needle in the bottle and the bottle upside down, check for air bubbles in the syringe. If you see any, push the plunger slowly in to push the air bubble back into the bottle. Keep the tip of the needle in the liquid and pull the plunger back again to fill to the 0.2 mL or 20 unit mark. 9. Do this again if necessary to eliminate air bubbles. 10.To protect your skin, inject each daily dose at a different body spot. 11.Choose an injection spot. Cleanse the injection spot with another alcohol wipe. 12.Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as you were instructed. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13.Holding the syringe as you would a pencil, thrust the needle all the way into the skin at a 90° angle. Push the plunger to administer the injection. 14.Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle at the same angle it was inserted. 15.Use the disposable syringe only once and dispose of it properly as you were instructed. Needles thrown into a garbage bag could accidentally stick someone. NEVER LEAVE SYRINGES, NEEDLES OR DRUGS WHERE CHILDREN CAN REACH THEM. SOME SPECIAL ADVICE • You may experience hot flashes when using LUPRON INJECTION (leuprolide acetate). During the first few weeks of treatment you may experience increased bone pain, increased difficulty in urinating, and less commonly but most importantly, you may experience the onset or aggravation of nerve symptoms. In any of these events, discuss the symptoms with your doctor. Like other treatment options, LUPRON may cause impotence. Notify your doctor if you develop new or worsened symptoms after beginning LUPRON treatment. • You may experience some irritation at the injection site, such as burning, itching or swelling. These reactions are usually mild and go away. If they do not, tell your doctor. • If you have experienced an allergic reaction to other drugs like LUPRON, you should not use this drug. • Do not stop taking your injections because you feel better. You need an injection every day to make sure LUPRON keeps working for you. • If you need to use an alternate to the syringe supplied with LUPRON, low-dose insulin syringes should be utilized. • When the drug level gets low, take special care to hold the bottle straight up and down and to keep the needle tip in liquid while pulling back on the plunger. • Do not try to get every last drop out of the bottle. This will increase the possibility of drawing air into the syringe and getting an incomplete dose. Some extra drug has been provided so that you can withdraw the recommended number of doses. • Tell your pharmacist when you will need LUPRON so it will be at the pharmacy when you need it. • Store below 77°F (25°C). Do not store near a radiator or other very warm place. Do not freeze. Protect from light; store vial in carton until use. • Do not leave your drug or hypodermic syringes where anyone can pick them up. • Keep this and all other medications out of reach of children. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured for Abbott Laboratories North Chicago, IL 60064, U.S.A. ® – Registered (No. 3612) December, 2008 © 2008 Abbott Laboratories For Pediatric Use LUPRON® INJECTION (leuprolide acetate) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl N-ethyl-L-prolinamide acetate (salt) with the following structural formula: structural formula LUPRON INJECTION is a sterile, aqueous solution intended for daily subcutaneous injection. It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Leuprolide acetate is not active when given orally. Pharmacokinetics A pharmacokinetic study of leuprolide acetate in children has not been performed. Absorption In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate. The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population. 1. Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal plates will not close prematurely. 2. Organ Growth. Reproductive organs will return to a prepubertal state. 3. Menses. Menses, if present, will cease. INDICATIONS AND USAGE LUPRON INJECTION is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria: 1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males. 2. Clinical diagnosis should be confirmed prior to initiation of therapy: • Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be understood. • Bone age advanced 1 year beyond the chronological age. 3. Baseline evaluation should also include: • Height and weight measurements. • Sex steroid levels. • Adrenal steroid level to exclude congenital adrenal hyperplasia. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor. • Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor. • Computerized tomography of the head to rule out intracranial tumor. CONTRAINDICATIONS 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature.1,2 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. (See PRECAUTIONS, Pregnancy, Teratogenic Effects section.) The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed (see CLINICAL PHARMACOLOGY section). Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature. PRECAUTIONS Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON INJECTION, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Parents Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the importance of continuous therapy. Adherence to daily drug administration schedules must be accepted if therapy is to be successful. Irregular dosing could restart the maturation process. • During the first 2 months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the physician. • Any irritation at the injection site should be reported to the physician immediately. If the child has experienced an allergic reaction to other drugs like LUPRON, this drug should not be used. • Report any unusual signs or symptoms to the physician, like continued pubertal changes, substantial mood swings or behavioral changes. Laboratory Tests Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6-12 months. Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see WARNINGS section). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses of 0.6 to 4 mg/kg (>100 times the clinical doses of 7.5 to 15 mg/month based on body surface area). There was a significant but not dose-related Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda increase of pancreatic islet-cell adenomas in females and of testes interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at daily dose as high as 60 mg/kg (>5000 times the clinical doses based on body surface area). Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS section) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Geriatric Use Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda See labeling for LUPRON INJECTION for the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials: Potential exacerbation of signs and symptoms during the first few weeks of treatment (see PRECAUTIONS section) is a concern in patients with rapidly advancing central precocious puberty. In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions considered not drug related are excluded. Number of Patients N = 421 (Percent) Body as a Whole General Pain 12 (3) Headache 11 (3) Injection Site Reactions Including Abscess* 37 (9) Cardiovascular System Vasodilation 9 (2) Integumentary System (Skin and Appendages) Acne/Seborrhea 13 (3) Rash Including Erythema Multiforme 12 (3) Nervous System Emotional Lability 19 (5) Urogenital System Vaginitis/Vaginal Bleeding/Vaginal Discharge 13 (3) * Most events were mild or moderate in severity. In those same studies, the following adverse reactions were reported in less than 2% of the patients. Body as a Whole – Aggravation of preexisting tumor and decreased vision, Allergic Reaction, Body Odor, Fever, Flu Syndrome, Hypertrophy, Infection; Cardiovascular System – Bradycardia, Hypertension, Peripheral Vascular Disorder, Syncope; Digestive System – Constipation, Dyspepsia, Dysphagia, Gingivitis, Increased Appetite, Nausea/Vomiting; Endocrine System - Accelerated Sexual Maturity, Feminization, Goiter; Hemic and Lymphatic System – Purpura; Metabolic and Nutritional Disorders – Growth Retarded, Peripheral Edema, Weight Gain; Musculoskeletal System – Arthralgia, Joint Disorder, Myalgia, Myopathy; Nervous System – Depression, Hyperkinesia, Nervousness, Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Somnolence; Respiratory System – Asthma, Epistaxis, Pharyngitis, Rhinitis, Sinusitis; Integumentary System (Skin and Appendages) - Alopecia, Hair Disorder, Hirutism, Leukoderma, Nail Disorder, Skin Hypertrophy; Urogenital System - Cervix Disorder/Neoplasm, Dysmenorrhea, Gynecomastia/Breast Disorders, Menstrual Disorder, Urinary Incontinence. Laboratory: The following laboratory events were reported as adverse reactions, antinuclear antibody present and increased sedimentation rate. Postmarketing During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Peripheral neuropathy, Convulsion, Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System –Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders; Urogenital System – Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. The effects on bone density in children are unknown. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON INJECTION and LUPRON DEPOT package inserts for adverse events reported in other patient populations. OVERDOSAGE In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials using leuprolide acetate in adult patients, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON INJECTION can be administered by a patient/parent or health care professional. The dose of LUPRON INJECTION must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio. After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters. The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy. As with other drugs administered by injection, the injection site should be varied periodically. Discontinuation of LUPRON INJECTION should be considered before age 11 for females and age 12 for males. The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose will be considered the maintenance dose. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple-dose vial. The vial is packaged as follows: • 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0074-3612-30. • Six-vial carton, NDC 0074-3612-34. • Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. • Use the syringes supplied with LUPRON INJECTION. Insulin syringes may be substituted for use with LUPRON INJECTION. U.S. Patent Nos. 4,005,063; 4,005,194. REFERENCES 1. Taylor, JD. Anaphylactic reaction to LHRH analogue, leuprorelin. Med J Australia 1994 Oct; 161(3): 455. 2. Letterie GS, et al. Recurrent anaphylaxis to a depot form of GnRH analogue. Obstet Gynecol 1991 Nov; 78: 943–946. Manufactured for Abbott Laboratories North Chicago, IL 60064, U.S.A. ® – Registered (No. 3612) ADMINISTERING THE INJECTION Read this booklet before injecting the medication. Read the complete instructions for injection. Abbott Laboratories North Chicago, IL 60064, U.S.A. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (No. 3612) December, 2008 © 2008 Abbott Laboratories Provided as an educational service by Abbott Laboratories Abbott Laboratories North Chicago, IL 60064, U.S.A. ADMINISTERING THE INJECTION 1. Wash hands thoroughly. usage illustrationusage illustration 2. Check the liquid in the container. It should look clear. DO NOT USE if it is not clear or if it has particles in it. If using a new bottle, flip off the plastic cover to expose the grey rubber stopper. Use an alcohol swab to cleanse the metal ring and rubber stopper on medication bottle every day, just before you use it. usage illustration 3. Remove outer wrapping from one syringe. usage illustration 4. Pull the syringe plunger back until its tip is at the proper mark. usage illustration 5. Uncover needle. Do not touch the needle. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda usage illustration usage illustrationusage illustration 6. Place the bottle on a clean, flat surface and push the needle through the center of the rubber stopper on the bottle. Push the plunger all the way in to inject air into the bottle. usage illustration 7. Keep the needle in the bottle. Lift the bottle and turn it straight upside down. Check to see that the needle tip is in the liquid. usage illustration 8. With the needle tip in the liquid, slowly pull back the plunger until syringe fills to the proper mark. If any bubbles appear in the syringe, remove them by pushing the plunger up slowly. With the needle tip still in the liquid, pull the plunger until it is once more at the proper mark. usage illustration 9. Choose a different injection site each day. Cleanse the injection site with a new alcohol swab. Hold the skin the way you were instructed. Slide the needle quickly all the way through the skin, into the subcutaneous tissue, at a 90° angle. 10. Push the plunger to inject the medication. Withdraw the needle at the same angle it was inserted (90°). Wipe the skin with an alcohol swab. 11. Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Dispose of the syringe and alcohol swabs as you were instructed. Remember: use the disposable syringe only once. Abbott Laboratories Reference ID: 2920484 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.153186	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019010s035lbl.pdf', 'application_number': 19010, 'submission_type': 'SUPPL ', 'submission_number': 35}
11,413	structural formula LUPRON® INJECTION (leuprolide acetate) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, subcutaneous administration of single daily doses of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and Reference ID: 3540421 dihydrotestosterone in males, and estrone and estradiol in pre-menopausal females). However, continuous daily administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. These decreases occur within two to four weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to five years. Leuprolide acetate is not active when given orally. Pharmacokinetics Absorption Bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Reference ID: 3540421 Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In a controlled study comparing LUPRON 1 mg/day given subcutaneously to DES (diethylstilbestrol), 3 mg/day, the survival rate for the two groups was comparable after two years of treatment. The objective response to treatment was also similar for the two groups. INDICATIONS AND USAGE LUPRON INJECTION (leuprolide acetate) is indicated in the palliative treatment of advanced prostatic cancer. CONTRAINDICATIONS 1. LUPRON INJECTION is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION: Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS Initially, LUPRON, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of LUPRON treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Safe use of leuprolide acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON, pregnancy must be excluded (see CONTRAINDICATIONS section). Periodic monitoring of serum testosterone and prostate-specific antigen (PSA) levels is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved. It should be noted that results of testosterone determinations are dependent on Reference ID: 3540421 assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. PRECAUTIONS Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS and ADVERSE REACTIONS sections). Patients with known allergies to benzyl alcohol, an ingredient of the drug's vehicle, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes. Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice. Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. Information for Patients See INFORMATION FOR PATIENTS which appears after the REFERENCE section. Laboratory Tests Response to leuprolide acetate should be monitored by measuring serum levels of testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. Castrate levels were reached within two to four weeks and once attained were maintained for as long as drug administration continued. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Reference ID: 3540421 Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults (≥ 18 years) with leuprolide acetate and similar analogs have shown full reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks. However, no clinical studies have been conducted with leuprolide acetate to assess the reversibility of fertility suppression. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/600 to 1/6 the human dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in major fetal malformations throughout gestation. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Reference ID: 3540421 Pediatric Use See labeling for LUPRON INJECTION for Pediatric Use for the safety and effectiveness in children with central precocious puberty. Geriatric Use In the clinical trials for LUPRON INJECTION, the majority (69%) of subjects studied were at least 65 years of age. Therefore, the labeling reflects the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. This transient increase was occasionally associated with a temporary worsening of signs and symptoms, usually manifested by an increase in bone pain (see WARNINGS section). In a few cases a temporary worsening of existing hematuria and urinary tract obstruction occurred during the first week. Temporary weakness and paresthesia of the lower limbs have been reported in a few cases. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction which, if aggravated, may lead to neurological problems or increase the obstruction. In a comparative trial of LUPRON INJECTION (leuprolide acetate) versus DES, in 5% or more of the patients receiving either drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug related are excluded. LUPRON (N=98) DES (N=101) Number of Reports Cardiovascular System Congestive heart failure 1 5 ECG changes/ischemia 19 22 High blood pressure 8 5 Murmur 3 8 Peripheral edema 12 30 Phlebitis/thrombosis 2 10 Gastrointestinal System Anorexia 6 5 Reference ID: 3540421 Constipation 7 9 Nausea/vomiting 5 17 Endocrine System Decreased testicular size 7 11 Gynecomastia/breast tenderness or pain 7 63 Hot flashes 55 12 Impotence 4 12 Hemic and Lymphatic System Anemia 5 5 Musculoskeletal System Bone pain 5 2 Myalgia 3 9 Central/Peripheral Nervous System Dizziness/lightheadedness 5 7 General pain 13 13 Headache 7 4 Insomnia/sleep disorders 7 5 Respiratory System Dyspnea 2 8 Sinus congestion 5 6 Integumentary System Dermatitis 5 8 Urogenital System Frequency/urgency 6 8 Hematuria 6 4 Urinary tract infection 3 7 Miscellaneous Asthenia 10 10 * Physiologic effect of decreased testosterone. In this same study, the following adverse reactions were reported in less than 5% of the patients on LUPRON. Cardiovascular System—Angina, Cardiac arrhythmias, Myocardial infarction, Pulmonary emboli; Gastrointestinal System—Diarrhea, Dysphagia, Gastrointestinal bleeding, Gastrointestinal disturbance, Peptic ulcer, Rectal polyps; Endocrine System—Libido decrease, Thyroid enlargement; Musculoskeletal System—Joint pain; Central/Peripheral Nervous System—Anxiety, Blurred vision, Lethargy, Memory disorder, Mood swings, Nervousness, Numbness, Paresthesia, Peripheral neuropathy, Syncope/blackouts, Taste disorders; Respiratory System—Cough, Pleural rub, Pneumonia, Pulmonary fibrosis; Integumentary System— Carcinoma of skin/ear, Dry skin, Ecchymosis, Hair loss, Itching, Local skin reactions, Pigmentation, Skin lesions; Urogenital System—Bladder spasms, Dysuria, Incontinence, Testicular pain, Urinary obstruction; Miscellaneous—Depression, Diabetes, Fatigue, Reference ID: 3540421 Fever/chills, Hypoglycemia, Increased BUN, Increased calcium, Increased creatinine, Infection/inflammation, Ophthalmologic disorders, Swelling (temporal bone). In an additional clinical trial and from long-term observation of both studies, the following additional adverse events (excluding those considered not drug related) were reported for patients receiving LUPRON. Cardiovascular System—Bradycardia, Carotid bruit, Extrasystole, Palpitations, Perivascular cuffing (eyes), Ruptured aortic aneurysm, Stroke, Tachycardia, Transient ischemic attack; Gastrointestinal System—Flatus, Dryness of mouth and throat, Hepatitis, Hepatomegaly, Occult blood (rectal exam), Rectal fistula/erythema; Endocrine System—Libido increase, Thyroid nodule; Musculoskeletal System—Ankylosing spondylosis, Arthritis, Blurred disc margins, Bone fracture, Muscle stiffness, Muscle tenderness, Pelvic fibrosis, Spasms/cramps; Central/Peripheral Nervous System—Auditory hallucinations/tinnitus, Decreased hearing, Decreased reflexes, Euphoria, Hyperreflexia, Loss of smell, Motor deficiency; Respiratory System—Chest tightness, Decreased breathing sounds, Hemoptysis, Pleuritic chest pain, Pulmonary infiltrate, Rales/rhonchi, Rhinitis, Strep throat, Wheezing/bronchitis; Integumentary System—Boil (pubic), Bruises, Hives, Keratosis, Mole, Shingles, Spiders; Urogenital System— Blisters on penis, Inguinal hernia, Penile swelling, Post void residual, Prostatic pain, Pyuria; Miscellaneous—Abdominal distention, Facial swelling/edema, Feet burning, Flu, Eyelid growth, Hypoproteinemia, Accidental injury, Knee effusion, Mass, Pallid, Sallow, Weakness. Postmarketing During postmarketing surveillance which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Myocardial infarction; Endocrine System - Diabetes; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Convulsion, Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Reference ID: 3540421 Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON INJECTION package inserts for other events reported in the same and different patient populations. OVERDOSAGE In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials with leuprolide acetate doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or acetic acid. Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple- dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable syringes and 28 alcohol swabs, NDC 0074-3612-30 and six-vial carton, NDC 0074-3612-34. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. Reference ID: 3540421 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63; 1172-1193. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd Ed.) Pittsburgh, PA: Oncology Nursing Society. INFORMATION FOR PATIENTS Be sure to consult your physician with any questions you may have or for information about LUPRON INJECTION (leuprolide acetate) and its use. WHAT IS LUPRON? LUPRON INJECTION (leuprolide acetate) is chemically similar to gonadotropin releasing hormone (GnRH or LH-RH) a hormone which occurs naturally in your body. Normally, your body releases small amounts of LH-RH and this leads to events which stimulate the production of sex hormones. However, when you inject LUPRON INJECTION (leuprolide acetate), the normal events that lead to sex hormone production are interrupted and testosterone is no longer produced by the testes. LUPRON must be injected because, like insulin which is injected by diabetics, LUPRON is inactive when taken by mouth. If you were to discontinue the drug for any reason, your body would begin making testosterone again. DIRECTIONS FOR USING LUPRON 1. Wash hands thoroughly with soap and water. 2. If using a new bottle for the first time, flip off the plastic cover to expose the grey rubber stopper. Wipe metal ring and rubber stopper with an alcohol wipe each time you use LUPRON. Check the liquid in the container. If it is not clear or has particles in it, DO NOT USE IT. Exchange it at your pharmacy for another container. 3. Remove outer wrapping from one syringe. Pull plunger back until the tip of the plunger is at the 0.2 mL or 20 unit mark. 4. Take cover off needle. Push the needle through the center of the rubber stopper on the LUPRON bottle. 5. Push the plunger all the way in to inject air into the bottle. 6. Keep the needle in the bottle and turn the bottle upside down. Check to make sure the tip of the needle is in the liquid. Slowly pull back on the plunger, until the syringe fills to the 0.2 mL or 20 unit mark. 7. Toward the end of a two-week period, the amount of LUPRON left in the bottle will be small. Take special care to hold the bottle straight and to keep the needle tip in liquid while pulling back on the plunger. Reference ID: 3540421 8. Keeping the needle in the bottle and the bottle upside down, check for air bubbles in the syringe. If you see any, push the plunger slowly in to push the air bubble back into the bottle. Keep the tip of the needle in the liquid and pull the plunger back again to fill to the 0.2 mL or 20 unit mark. 9. Do this again if necessary to eliminate air bubbles. 10. To protect your skin, inject each daily dose at a different body spot. 11. Choose an injection spot. Cleanse the injection spot with another alcohol wipe. 12. Hold the syringe in one hand. Hold the skin taut, or pull up a little flesh with the other hand, as you were instructed. 13. Holding the syringe as you would a pencil, thrust the needle all the way into the skin at a 90° angle. Push the plunger to administer the injection. 14. Hold an alcohol wipe down on your skin where the needle is inserted and withdraw the needle at the same angle it was inserted. 15. Use the disposable syringe only once and dispose of it properly as you were instructed. Needles thrown into a garbage bag could accidentally stick someone. NEVER LEAVE SYRINGES, NEEDLES OR DRUGS WHERE CHILDREN CAN REACH THEM. SOME SPECIAL ADVICE • You may experience hot flashes when using LUPRON INJECTION (leuprolide acetate). During the first few weeks of treatment you may experience increased bone pain, increased difficulty in urinating, and less commonly but most importantly, you may experience the onset or aggravation of nerve symptoms. In any of these events, discuss the symptoms with your doctor. Like other treatment options, LUPRON may cause impotence. Notify your doctor if you develop new or worsened symptoms after beginning LUPRON treatment. • You may experience some irritation at the injection site, such as burning, itching or swelling. These reactions are usually mild and go away. If they do not, tell your doctor. • If you have experienced an allergic reaction to other drugs like LUPRON, you should not use this drug. • Do not stop taking your injections because you feel better. You need an injection every day to make sure LUPRON keeps working for you. • If you need to use an alternate to the syringe supplied with LUPRON, low-dose insulin syringes should be utilized. • When the drug level gets low, take special care to hold the bottle straight up and down and to keep the needle tip in liquid while pulling back on the plunger. • Do not try to get every last drop out of the bottle. This will increase the possibility of drawing air into the syringe and getting an incomplete dose. Some extra drug has been provided so that you can withdraw the recommended number of doses. • Tell your pharmacist when you will need LUPRON so it will be at the pharmacy when you need it. • Store below 77°F (25°C). Do not store near a radiator or other very warm place. Do not freeze. Protect from light; store vial in carton until use. • Do not leave your drug or hypodermic syringes where anyone can pick them up. • Keep this and all other medications out of reach of children. Reference ID: 3540421 Manufactured for AbbVie Inc. North Chicago, IL 60064, U.S.A. Rev. 07/2014 For Pediatric Use LUPRON® INJECTION (leuprolide acetate) Rx only DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5- oxo -L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON INJECTION is a sterile, aqueous solution intended for daily subcutaneous injection. It is available in a 2.8 mL multiple dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. CLINICAL PHARMACOLOGY Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Reference ID: 3540421 Pharmacokinetics A pharmacokinetic study of leuprolide acetate in children has not been performed. Absorption In adults, bioavailability by subcutaneous administration is comparable to that by intravenous administration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy adult male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. Metabolism In healthy adult male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to three adult patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined. Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. Reference ID: 3540421 CLINICAL STUDIES In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of leuprolide acetate. The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population. 1. Skeletal Growth. A measurable increase in body length can be noted since the epiphyseal plates will not close prematurely. 2. Organ Growth. Reproductive organs will return to a prepubertal state. 3. Menses. Menses, if present, will cease. INDICATIONS AND USAGE LUPRON INJECTION is indicated in the treatment of children with central precocious puberty. Children should be selected using the following criteria: 1. Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males. 2. Clinical diagnosis should be confirmed prior to initiation of therapy: • Confirmation of diagnosis by a pubertal response to a GnRH stimulation test. The sensitivity and methodology of this assay must be understood. • Bone age advanced 1 year beyond the chronological age. 3. Baseline evaluation should also include: • Height and weight measurements. • Sex steroid levels. • Adrenal steroid level to exclude congenital adrenal hyperplasia. • Beta human chorionic gonadotropin level to rule out a chorionic gonadotropin secreting tumor. • Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor. • Computerized tomography of the head to rule out intracranial tumor. CONTRAINDICATIONS 1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON INJECTION. Reports of anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. 2. LUPRON is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON may cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. (See PRECAUTIONS, Pregnancy, Teratogenic Effects section.) The effects on fetal mortality are expected consequences of the alterations in hormonal levels Reference ID: 3540421 brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. If this drug is administered during pregnancy or if the patient becomes pregnant while taking any formulation of LUPRON, the patient should be apprised of the potential hazard to the fetus. WARNINGS During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed (see CLINICAL PHARMACOLOGY section). Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature. PRECAUTIONS Patients with known allergies to benzyl alcohol, an ingredient of the vehicle of LUPRON INJECTION, may present symptoms of hypersensitivity, usually local, in the form of erythema and induration at the injection site. Information for Parents Prior to starting therapy with LUPRON INJECTION, the parent or guardian must be aware of the importance of continuous therapy. Adherence to daily drug administration schedules must be accepted if therapy is to be successful. Irregular dosing could restart the maturation process. • During the first 2 months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the physician. • Any irritation at the injection site should be reported to the physician immediately. If the child has experienced an allergic reaction to other drugs like LUPRON, this drug should not be used. • Report any unusual signs or symptoms to the physician, like continued pubertal changes, substantial mood swings or behavioral changes. Laboratory Tests Response to leuprolide acetate should be monitored 1-2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6-12 months. Sex steroids may increase or rise above prepubertal levels if the dose is inadequate (see WARNINGS section). Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Reference ID: 3540421 Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics section. Drug/Laboratory Test Interactions Administration of leuprolide acetate in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored within 4 to 12 weeks after treatment is discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses of 0.6 to 4 mg/kg (>100 times the clinical doses of 7.5 to 15 mg/month based on body surface area). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testes interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate- induced tumors or pituitary abnormalities were observed at daily dose as high as 60 mg/kg (>5000 times the clinical doses based on body surface area). Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown. Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS section) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1200 to 1/12 the human pediatric dose) to rabbits, LUPRON produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON in rabbits and with the highest dose in rats. Reference ID: 3540421 Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers. Geriatric Use See labeling for LUPRON INJECTION for the pharmacokinetics, efficacy and safety of LUPRON in this population. ADVERSE REACTIONS Clinical Trials: Potential exacerbation of signs and symptoms during the first few weeks of treatment (see PRECAUTIONS section) is a concern in patients with rapidly advancing central precocious puberty. In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions considered not drug related are excluded. Number of Patients N = 421 (Percent) Body as a Whole General Pain 12 (3) Headache 11 (3) Injection Site Reactions Including Abscess* 37 (9) Cardiovascular System Vasodilation 9 (2) Integumentary System (Skin and Appendages) Acne/Seborrhea 13 (3) Rash Including Erythema Multiforme 12 (3) Nervous System Emotional Lability 19 (5) Urogenital System Vaginitis/Vaginal Bleeding/Vaginal Discharge 13 (3) * Most events were mild or moderate in severity. In those same studies, the following adverse reactions were reported in less than 2% of the patients. Reference ID: 3540421 Body as a Whole – Aggravation of preexisting tumor and decreased vision, Allergic Reaction, Body Odor, Fever, Flu Syndrome, Hypertrophy, Infection; Cardiovascular System – Bradycardia, Hypertension, Peripheral Vascular Disorder, Syncope; Digestive System – Constipation, Dyspepsia, Dysphagia, Gingivitis, Increased Appetite, Nausea/Vomiting; Endocrine System - Accelerated Sexual Maturity, Feminization, Goiter; Hemic and Lymphatic System – Purpura; Metabolic and Nutritional Disorders – Growth Retarded, Peripheral Edema, Weight Gain; Musculoskeletal System – Arthralgia, Joint Disorder, Myalgia, Myopathy; Nervous System – Depression, Hyperkinesia, Nervousness, Somnolence; Respiratory System – Asthma, Epistaxis, Pharyngitis, Rhinitis, Sinusitis; Integumentary System (Skin and Appendages) Alopecia, Hair Disorder, Hirsutism, Leukoderma, Nail Disorder, Skin Hypertrophy; Urogenital System - Cervix Disorder/Neoplasm, Dysmenorrhea, Gynecomastia/Breast Disorders, Menstrual Disorder, Urinary Incontinence. Laboratory: The following laboratory events were reported as adverse reactions, antinuclear antibody present and increased sedimentation rate. Postmarketing During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse events were reported. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely (incidence rate of about 0.002%) reported. Rash, urticaria, and photosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Cardiovascular System – Hypotension, Pulmonary embolism; Gastrointestinal System – Hepatic dysfunction; Hemic and Lymphatic System – Decreased WBC; Integumentary System – Hair growth; Central/Peripheral Nervous System – Peripheral neuropathy, Convulsion, Spinal fracture/paralysis, Hearing disorder; Miscellaneous – Hard nodule in throat, Weight gain, Increased uric acid; Musculoskeletal System – Tenosynovitis-like symptoms; Respiratory System – Respiratory disorders; Urogenital System – Prostate pain. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least six months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. The effects on bone density in children are unknown. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Reference ID: 3540421 See other LUPRON INJECTION and LUPRON DEPOT package inserts for adverse events reported in other patient populations. OVERDOSAGE In rats, subcutaneous administration of 125 to 250 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon. In early clinical trials using leuprolide acetate in adult patients, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON INJECTION can be administered by a patient/parent or health care professional. The dose of LUPRON INJECTION must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio. After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters. The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy. As with other drugs administered by injection, the injection site should be varied periodically. Discontinuation of LUPRON INJECTION should be considered before age 11 for females and age 12 for males. The recommended starting dose is 50 mcg/kg/day administered as a single subcutaneous injection. If total downregulation is not achieved, the dose should be titrated upward by 10 mcg/kg/day. This dose will be considered the maintenance dose. Follow the pictorial directions on the reverse side of this package insert for administration. NOTE: As with other parenteral products, inspect the solution for discoloration and particulate matter before each use. HOW SUPPLIED LUPRON INJECTION (leuprolide acetate) is a sterile solution supplied in a 2.8 mL multiple- dose vial. The vial is packaged as follows: 14 Day Patient Administration Kit with 14 disposable Reference ID: 3540421 syringes (Use the syringes supplied with LUPRON INJECTION) and 28 alcohol swabs, NDC 0074-3612-30 and six-vial carton, NDC 0074-3612-34. Store below 77°F (25°C). Do not freeze. Protect from light; store vial in carton until use. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63; 1172-1193. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd Ed.) Pittsburgh, PA: Oncology Nursing Society. Manufactured for AbbVie Inc. North Chicago, IL 60064, U.S.A. ADMINISTERING THE INJECTION Read this booklet before injecting the medication. Read the complete instructions for injection. AbbVie Inc. North Chicago, IL 60064, U.S.A. Rev. 07/2014 Provided as an educational service by AbbVie Inc. AbbVie Inc. North Chicago, IL 60064, U.S.A. Reference ID: 3540421 ADMINISTERING THE INJECTION 1. Wash hands thoroughly. 2. Check the liquid in the container. It should look clear. DO NOT USE if it is not clear or if it has particles in it. If using a new bottle, flip off the plastic cover to expose the grey rubber stopper. Use an alcohol swab to cleanse the metal ring and rubber stopper on medication bottle every day, just before you use it. Reference ID: 3540421 3. Remove outer wrapping from one syringe. 4. Pull the syringe plunger back until its tip is at the proper mark. 5. Uncover needle. Do not touch the needle. 6. Reference ID: 3540421 Place the bottle on a clean, flat surface and push the needle through the center of the rubber stopper on the bottle. Push the plunger all the way in to inject air into the bottle. 7. Keep the needle in the bottle. Lift the bottle and turn it straight upside down. Check to see that the needle tip is in the liquid. 8. With the needle tip in the liquid, slowly pull back the plunger until syringe fills to the proper mark. If any bubbles appear in the syringe, remove them by pushing the plunger up slowly. With the needle tip still in the liquid, pull the plunger until it is once more at the proper mark. Reference ID: 3540421 9. Choose a different injection site each day. Cleanse the injection site with a new alcohol swab. Hold the skin the way you were instructed. Slide the needle quickly all the way through the skin, into the subcutaneous tissue, at a 90° angle. 10. Push the plunger to inject the medication. Withdraw the needle at the same angle it was inserted (90°). Wipe the skin with an alcohol swab. Reference ID: 3540421 11. Dispose of the syringe and alcohol swabs as you were instructed. Remember: use the disposable syringe only once. Reference ID: 3540421	custom-source	2025-02-12T13:45:12.277575	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019010s037lbl.pdf', 'application_number': 19010, 'submission_type': 'SUPPL ', 'submission_number': 37}
11,416	07-19-47-258 3% and 5% Sodium Chloride Injection, USP in VIAFLEX Plastic Container Description 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Clinical Pharmacology 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings 3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage. 3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection, USP may result in sodium retention. Precautions Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5% Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Do not administer unless solution is clear and seal is intact. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Table 1 Osmolarity (mOsmol/L) (calc) Chloride Sodium Chloride USP (NaCl) Composition (g/L) Ionic Concentration (mEq/L) Sodium pH 3% Sodium Chloride Injection, USP 5% Sodium Chloride Injection, USP Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. 30 513 513 1027 5.0 (4.5 to 7.0) 50 856 856 1711 5.0 (4.5 to 7.0) size (mL) 500 500 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 3% and 5% Sodium Chloride Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC Product Name 2B1353 500 0338-0054-03 3% Sodium Chloride Injection, USP 2B1373 500 0338-0056-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25oC); brief exposure up to 40oC does not adversely affect the product. Directions for Use of VIAFLEX Plastic Container Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Warning: Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA 07-19-47-258 Rev. March 2005 *BAR CODE POSITION ONLY 071947258 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.371573	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019022s021lbl.pdf', 'application_number': 19022, 'submission_type': 'SUPPL ', 'submission_number': 21}
11,415	NDA 19-018/S-018 Page 5 Y36-002-484 PACKAGE INSERT TrophAmine® (Amino Acid Injections) Protect from light until use. Rx only DESCRIPTION TrophAmine (6% and 10% Amino Acid Injections) are sterile, nonpyrogenic, hypertonic solutions containing crystalline amino acids. All amino acids designated USP are the “L”-isomer with the exception of Glycine USP which does not have an isomer. Each 100 mL contains: Essential Amino Acids 6% 10% Isoleucine USP 0.49 g 0.82 g Leucine USP 0.84 g 1.4 g Lysine 0.49 g 0.82 g (added as Lysine Acetate USP 0.69 g 1.2 g) Methionine USP 0.20 g 0.34 g Phenylalanine USP 0.29 g 0.48 g Threonine USP 0.25 g 0.42 g Tryptophan USP 0.12 g 0.20 g Valine USP 0.47 g 0.78 g Cysteine <0.014 g <0.016 g (as Cysteine HCI•H2O USP <0.020 g <0.024 g) Histidine USP1 0.29 g 0.48 g Tyrosine1 0.14 g 0.24 g (added as Tyrosine USP 0.044 g 0.044 g and N-Acetyl-L-Tyrosine 0.12 g 0.24 g) Nonessential Amino Acids Alanine USP 0.32 g 0.54 g Arginine USP 0.73 g 1.2 g Proline USP 0.41 g 0.68 g Serine USP 0.23 g 0.38 g Glycine USP 0.22 g 0.36 g L-Aspartic Acid 0.19 g 0.32 g L-Glutamic Acid 0.30 g 0.50 g Taurine2, 3 0.015 g 0.025 g Sodium Metabisulfite NF (as an antioxidant) <0.050 g <0.050 g Water for Injection USP qs qs pH adjusted with Glacial Acetic Acid USP pH: 5.5 (5.0-6.0) Calc. Osmolarity (mOsmol/liter) 525 875 Total Amino Acids (grams/liter) 60 100 Total Nitrogen (grams/liter) 9.3 15.5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 6 Protein Equivalent (grams/liter) 58 97 Electrolytes (mEq/liter) Sodium 5 5 Acetate (CH3COO–) 54.4 97 Chloride <3 <3 Provided as acetic acid and Iysine acetate. 1 Holt LE, Snyderman SE: The amino acid requirements of infants. JAMA 1961; 175(2):124-127. 2 Rigo J, Senterre J: Is taurine essential for the neonates? Biol Neonate 1977; 32:73-76. 3 Gaull G, Sturman JA, Räihä NCR: Development of mammalian sulfur metabolism: Absence of cystothionase in human fetal tissues. Pediatr Res 1972; 6:538-547. CLINICAL PHARMACOLOGY TrophAmine provides a mixture of essential and nonessential amino acids as well as taurine and a soluble form of tyrosine, N-Acetyl-L-Tyrosine (NAT). This amino acid composition has been specifically formulated to provide a well tolerated nitrogen source for nutritional support and therapy for infants and young pediatric patients. When administered in conjunction with cysteine hydrochloride, TrophAmine results in the normalization of the plasma amino acid concentrations to a profile consistent with that of a breast-fed infant. The rationale for TrophAmine® (Amino Acid Injections) is based on the observation of inadequate levels of essential amino acids in the plasma of infants receiving total parenteral nutrition (TPN) using conventional amino acid solutions. The TrophAmine formula was developed through the application of specific pharmacokinetic multiple regression analysis relating amino acid intake to the resulting plasma amino acid concentrations. Clinical studies in infants and young pediatric patients who required TPN therapy showed that infusion of TrophAmine with a cysteine hydrochloride admixture resulted in a normalization of the plasma amino acid concentrations. In addition, weight gains, nitrogen balance, and serum protein concentrations were consistent with an improving nutritional status. When infused with hypertonic dextrose as a calorie source, supplemented with cysteine hydrochloride, electrolytes, vitamins, and minerals, TrophAmine provides total parenteral nutrition in infants and young pediatric patients, with the exception of essential fatty acids. It is thought that the acetate from Iysine acetate and acetic acid, under the conditions of parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence seems to support this thinking; however, confirmatory experimental evidence is not available. The amounts of sodium and chloride present in TrophAmine are not of clinical significance. The addition of cysteine hydrochloride will contribute to the chloride load. The electrolyte content of any additives that are introduced should be carefully considered and included in total input computations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 7 INDICATIONS AND USAGE TrophAmine is indicated for the nutritional support of infants (including those of low birth weight) and young pediatric patients requiring TPN via either central or peripheral infusion routes. Parenteral nutrition with TrophAmine is indicated to prevent nitrogen and weight loss or treat negative nitrogen balance in infants and young pediatric patients where (1) the alimentary tract, by the oral, gastrostomy, or jejunostomy route, cannot or should not be used, or adequate protein intake is not feasible by these routes; (2) gastrointestinal absorption of protein is impaired; or (3) protein requirements are substantially increased as with extensive burns. Dosage, route of administration, and concomitant infusion of non-protein calories are dependent on various factors, such as nutritional and metabolic status of the patient, anticipated duration of parenteral nutritional support, and vein tolerance. See WARNINGS, PRECAUTIONS, Pediatric Use, and DOSAGE AND ADMINISTRATION. Central Venous Nutrition Central venous infusion should be considered when amino acid solutions are to be admixed with hypertonic dextrose to promote protein synthesis in hypercatabolic or severely depleted infants, or those requiring long-term parenteral nutrition. Peripheral Parenteral Nutrition For moderately catabolic or depleted patients in whom the central venous route is not indicated, diluted amino acid solutions mixed with 5-10% dextrose solutions may be infused by peripheral vein, supplemented, if desired, with fat emulsion. In pediatric patients, the final solution should not exceed twice normal serum osmolarity (718 mOsmol/L). CONTRAINDICATIONS TrophAmine is contraindicated in patients with untreated anuria, hepatic coma, inborn errors of amino acid metabolism, including those involving branched chain amino acid metabolism such as maple syrup urine disease and isovaleric acidemia, or hypersensitivity to one or more amino acids present in the solution. WARNINGS Safe, effective use of parenteral nutrition requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of the complications which can occur. Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring of parenteral nutrition. Studies should include blood sugar, serum proteins, kidney and liver function tests, electrolytes, hemogram, carbon dioxide content, serum osmolalities, blood cultures, and blood ammonia levels. WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 8 Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Administration of amino acids in the presence of impaired renal function or gastrointestinal bleeding may augment an already elevated blood urea nitrogen. Patients with azotemia from any cause should not be infused with amino acids without regard to total nitrogen intake. Administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the solutions. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the solutions. Administration of amino acid solutions to a patient with hepatic insufficiency may result in plasma amino acid imbalances, hyperammonemia, prerenal azotemia, stupor and coma. Hyperammonemia is of special significance in infants as its occurrence in the syndrome caused by genetic metabolic defects is sometimes associated, although not necessarily in a causal relationship, with mental retardation. This reaction appears to be dose related and is more likely to develop during prolonged therapy. It is essential that blood ammonia be measured frequently in infants. The mechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinically impaired liver function. Conservative doses of amino acids should be given, dictated by the nutritional status of the patient. Should symptoms of hyperammonemia develop, amino acid administration should be discontinued and the patient’s clinical status reevaluated. This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS General Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements. Strongly hypertonic nutrient solutions should be administered via an intravenous catheter placed in a central vein, preferably the superior vena cava. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 9 Special care must be taken when giving hypertonic dextrose to a diabetic or pre-diabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required. Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma, and death. Administration of amino acids without carbohydrates may result in the accumulation of ketone bodies in the blood. Correction of this ketonemia may be achieved by the administration of carbohydrate. Peripheral administration of TrophAmine® (Amino Acid Injections) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusions or change infusion site and initiate appropriate treatment. In pediatric patients, the final solution should not exceed twice normal serum osmolarity (718 mOsmol/L). Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum. TrophAmine® (Amino Acid Injections) contains less than 3 mEq chloride per liter. TrophAmine contains no added phosphorus. Patients, especially those with hypophosphatemia, may require the addition of phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Use only if solution is clear and vacuum is present. Drug product contains no more than 25 µg/L of aluminum. Laboratory Tests Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring during administration. Laboratory tests should include measurement of blood sugar, electrolyte, and serum protein concentrations; kidney and liver function tests; and evaluation of acid-base balance and fluid balance. Other laboratory tests may be suggested by the patient’s condition. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 10 Drug Interactions Some additives may be incompatible. Consult with pharmacist. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store. Carcinogenesis, Mutagenesis, Impairment of Fertility No in vitro or in vivo carcinogenesis, mutagenesis, or fertility studies have been conducted with TrophAmine. Pregnancy - Teratogenic Effects - Pregnancy Category C. Animal reproduction studies have not been conducted with TrophAmine (Amino Acid Injections). It is also not known whether TrophAmine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TrophAmine should be given to a pregnant woman only if clearly needed. Labor and Delivery Information is unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised with TrophAmine if administered to a nursing woman. Pediatric Use As in all cases of fluid and electrolyte replacement and parenteral nutrition, careful monitoring and special caution is required in pediatric use, especially in pediatric patients with renal failure, acute sepsis, or low birth weight. The total volume of nutritional fluid and the rate of administration in each patient will be based on individually calculated maintenance and/or replacement fluid requirements, and nutritional needs, and will vary with the child’s age, body weight and renal function. In neonates and very small infants, particularly careful monitoring will be required to maintain fluid and electrolyte balance, including monitoring of blood glucose. See INDICATIONS AND USAGE, WARNINGS, and DOSAGE AND ADMINISTRATION. Geriatric Use TrophAmine has not been studied in geriatric patients. Elderly patients are known to be more prone to fluid overload and electrolyte imbalance than younger patients. This may be related to impairment of renal function which is more frequent in an elderly population. As a result the need for careful monitoring of fluid and electrolyte therapy is greater in the elderly. All patients, including the elderly, require an individual dose of all parenteral nutrition products to be determined by the physician on an individual case-by-case basis, which will be based on body weight, clinical condition and the results of laboratory monitoring tests. There is no specific geriatric dose. See WARNINGS. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 11 Special Precautions for Central Venous Nutrition Administration by central venous catheter should be used only by those familiar with this technique and its complications. Central venous nutrition may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure, including solution preparation, administration, and patient monitoring. It is essential that a carefully prepared protocol, based on current medical practices, be followed, preferably by an experienced team. Although a detailed discussion of the complications is beyond the scope of this insert, the following summary lists those based on current literature: Technical. The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion as well as recognition and treatment of complications. For details of techniques and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air and catheter embolus. Septic. The constant risk of sepsis is present during central venous nutrition. Since contaminated solutions and infusion catheters are potential sources of infection, it is imperative that the preparation of parenteral nutrition solutions and the placement and care of catheters be accomplished under controlled aseptic conditions. Solutions should ideally be prepared in the hospital pharmacy in a laminar flow hood. The key factor in their preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and subsequent admixtures. Parenteral nutrition solutions should be used promptly after mixing. Any storage should be under refrigeration for as brief a time as possible. Administration time for a single bottle and set should never exceed 24 hours. Consult the medical literature for a discussion of the management of sepsis during central venous nutrition. In brief, typical management includes replacing the solution being administered with a fresh container and set, and the remaining contents are cultured for bacterial or fungal contamination. If sepsis persists and another source of infection is not identified, the catheter is removed, the proximal tip cultured, and a new catheter reinserted when the fever has subsided. Non-specific, prophylactic antibiotic treatment is not recommended. Clinical experience indicates that the catheter is likely to be the prime source of infection as opposed to aseptically prepared and properly stored solutions. Metabolic. The following metabolic complications have been reported: metabolic acidosis, hypophosphatemia, alkalosis, hyperglycemia and glycosuria, osmotic diuresis and dehydration, rebound hypoglycemia, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances, and hyperammonemia in pediatric patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 12 Frequent clinical evaluation and laboratory determinations are necessary, especially during the first few days of venous nutrition, to prevent or minimize these complications. ADVERSE REACTIONS See “WARNINGS” and “Special Precautions for Central Venous Nutrition.” Reactions reported in clinical studies as a result of infusion of the parenteral fluid were water weight gain, edema, increase in BUN, and mild acidosis. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. Local reaction at the infusion site, consisting of a warm sensation, erythema, phlebitis and thrombosis, have been reported with peripheral amino acid infusions, especially if other substances are also administered through the same site. If electrolyte supplementation is required during peripheral infusion, it is recommended that additives be administered throughout the day in order to avoid possible venous irritation. Irritating additive medications may require injection at another site and should not be added directly to the amino acid infusate. Symptoms may result from an excess or deficit of one or more of the ions present in the solution; therefore, frequent monitoring of electrolyte levels is essential. Phosphorus deficiency may lead to impaired tissue oxygenation and acute hemolytic anemia. Relative to calcium, excessive phosphorus intake can precipitate hypocalcemia with cramps, tetany and muscular hyperexcitability. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s condition and institute appropriate corrective treatment. DOSAGE AND ADMINISTRATION The objective of nutritional management of infants and young pediatric patients is the provision of sufficient amino acid and caloric support for protein synthesis and growth. The total daily dose of TrophAmine® (Amino Acid Injections) depends on daily protein requirements and on the patient’s metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 13 Dosage should also be guided by the patient’s fluid intake limits and glucose and nitrogen tolerances, as well as by metabolic and clinical response. Recommendations for allowances of protein in infant nutrition have ranged from 2 to 4 grams of protein per kilogram of body weight per day (2.0 to 4.0 g/kg/day).4 The recommended dosage of TrophAmine is 2.0 to 2.5 grams of amino acids per kilogram of body weight per day (2.0 to 2.5 g/kg/day) for infants up to 10 kilograms. For infants and young pediatric patients larger than 10 kilograms, the total dosage of amino acids should include the 20 to 25 grams/day for the first 10 kg of body weight plus 1.0 to 1.25 g/day for each kg of body weight over 10 kilograms. Typically, TrophAmine is admixed with B. Braun’s 50% or 70% Dextrose Injection USP supplemented with electrolytes and vitamins and administered continuously over a 24 hour period. Total daily fluid intake should be appropriate for the patient’s age and size. A fluid dose of 125 mL per kilogram body weight per day is appropriate for most infants on TPN. Although nitrogen requirements may be higher in severely hypercatabolic or depleted patients, provision of additional nitrogen may not be possible due to fluid intake limits, nitrogen, or glucose intolerance. Cysteine is considered to be an essential amino acid in infants and young pediatric patients. An admixture of cysteine hydrochloride to the TPN solution is therefore recommended. Based on clinical studies, the recommended dosage is 1.0 mmole of L-cysteine hydrochloride monohydrate per kilogram of body weight per day. In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose solutions are abruptly discontinued. Fat emulsion coadministration should be considered when prolonged (more than 5 days) parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.). Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat free TPN. The provision of sufficient intracellular electrolytes, principally potassium, magnesium, and phosphate, is required for optimum utilization of amino acids. In addition, sufficient quantities of the major extracellular electrolytes sodium, calcium, and chloride, must be given. In patients with hyperchloremic or other metabolic acidoses, sodium and potassium may be added as the acetate salts to provide bicarbonate precursor. The electrolyte content of TrophAmine must be considered when calculating daily electrolyte intake. Serum electrolytes, including magnesium and phosphorus, should be monitored frequently. Appropriate vitamins, minerals and trace elements should also be provided. Central Venous Nutrition. Hypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the superior vena cava. Initial infusion rates should be slow, and gradually increased to the recommended 60-125 mL per kilogram body weight per day. If administration rate should fall behind schedule, no attempt to “catch up” to planned intake This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 14 should be made. In addition to meeting protein needs, the rate of administration, particularly during the first few days of therapy, is governed by the patient’s glucose tolerance. Daily intake of amino acids and dextrose should be increased gradually to the maximum required dose as indicated by frequent determinations of glucose levels in blood and urine. Peripheral Parenteral Nutrition. For patients in whom the central venous route is not indicated and who can consume adequate calories enterally, TrophAmine® (Amino Acid Injections) may be administered by peripheral vein with or without parenteral carbohydrate calories. Such infusates can be prepared by dilution with B. Braun’s Sterile Water for Injection or 5%-10% Dextrose Injection to prepare isotonic or slightly hypertonic solutions for peripheral infusion. It is essential that peripheral infusion be accompanied by adequate caloric intake. In pediatric patients, the final solution should not exceed twice normal serum osmolarity (718 mOsmol/L). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. TrophAmine may be admixed with solutions which contain phosphate or which have been supplemented with phosphate. The presence of calcium and magnesium ions in an additive solution should be considered when phosphate is also present, in order to avoid precipitation. Care must be taken to avoid incompatible admixtures. Consult with pharmacist. 4 Suskind RM: Textbook of Pediatric Nutrition, Raven Press, New York, 1981. HOW SUPPLIED TrophAmine is supplied sterile and nonpyrogenic in 500 mL glass containers with solid stoppers. NDC Cat. No. Units per Case TROPHAMINE (6% AMINO ACID INJECTION) 0264-9361-55 S9361-SS 12 TROPHAMINE (10% AMINO ACID INJECTION) 0264-9341-55 S9341-SS 6 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product. Protect from light until use. Revised: May 2003 U.S. Patent No. 4,491,589 TrophAmine is a registered trademark of B. Braun Medical Inc. Made in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 15 Directions for Use of B. Braun Glass Containers with Solid Stoppers Designed for use with a vented set. Before use, perform the following checks: 1. Inspect each container. Read the label. Ensure solution is the one ordered and is within the expiration date. Check the security of bail and band. 2. Invert container and carefully inspect the solution in good light for cloudiness, haze, or particulate matter; check the bottle for cracks or other damage. In checking for cracks, do not be confused by normal surface marks and seams on the bottom and sides of the bottle. These are not flaws. Look for bright reflections that have depth and penetrate into the wall of the bottle. Reject any such bottle. 3. To remove the outer closure, lift the tear tab and pull up, over, and down until it is below the stopper (See Figure 1). Use a circular pulling motion on the tab until it breaks away. Tear Tab Figure 1 4. Grasp and remove the metal disk, exercising caution not to touch the exposed sterile stopper surface. Warning: Some additives may be incompatible. Consult with pharmacist. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store. 5. Refer to Directions for Use of the set being used. Insert the set spike into the large round outlet port of the stopper and hang container. 6. After admixture and during administration, reinspect the solution frequently. If any evidence of solution contamination or instability is found or if the patient exhibits any signs of fever, chills or other reactions not readily explainable, discontinue administration immediately and notify the physician. 7. When adding medication to the container during administration, swab the triangular medication site, inject medication and mix thoroughly by gentle agitation. 8. Spiking, additions, or transfers should be made immediately after exposing the sterile stopper surface. Check for vacuum at first puncture of stopper. Admixture by needle or syringe should be made through the triangular This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-018/S-018 Page 16 (∇) medication site; contents should be drawn by vacuum into the bottle. Admixture by spiked vial should be through the outlet port (See Figure 2). If contents of initial addition are not drawn into the bottle, vacuum is not present and the unit should be discarded. Each addition/transfer will reduce the vacuum remaining in the bottle. After metal disk is removed Figure 6 9. If the first puncture of the stopper is the administration set spike, insert the spike fully into the outlet port of the stopper and promptly invert the bottle. Verify vacuum by observing rising air bubbles. Do not use the bottle if vacuum is not present. 10. If admixture or set insertion is not performed immediately following removal of protective metal disk, swab stopper surface. B. Braun Medical Inc. Irvine CA USA 92614-5895 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.578273	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19018scs018_trophamine_lbl.pdf', 'application_number': 19018, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,418	---------- PERIDEX - chlorhexidine gluconate mouthwash 3M Peridex™ (CHLORHEXIDINE GLUCONATE 0.12%) ORAL RINSE DESCRIPTION Peridex is an oral rinse containing 0.12% chlorhexidine gluconate (1, 11-hexamethylene bis [5-(p-chlorophenyl) biguanide] di-D-gluconate) in a base containing water, 11.6% alcohol, glycerin, PEG-40 sorbitan diisostearate, flavor, sodium saccharin, and FD&C Blue No. 1. Peridex oral rinse is a near-neutral solution (pH range 5-7). Chlorhexidine gluconate is a salt of chlorhexidine and gluconic acid. Its chemical structure is: structural formula CLINICAL PHARMACOLOGY Peridex provides antimicrobial activity during oral rinsing. The clinical significance of Peridex's antimicrobial activities is not clear. Microbiological sampling of plaque has shown a general reduction of counts of certain assayed bacteria, both aerobic and anaerobic, ranging from 54-97% through six months use. Use of Peridex oral rinse in a six month clinical study did not result in any significant changes in bacteria resistance, overgrowth of potentially opportunistic organisms or other adverse changes in the oral microbial ecosystem. Three months after Peridex use was discontinued, the number of bacteria in plaque had returned to baseline levels and resistance of plaque bacteria to chlorhexidine gluconate was equal to that at baseline. PHARMACOKINETICS Pharmacokinetic studies with Peridex indicate approximately 30% of the active ingredient, chlorhexidine gluconate, is retained in the oral cavity following rinsing. This retained drug is slowly released into the oral fluids. Studies conducted on human subjects and animals demonstrate chlorhexidine gluconate is poorly absorbed from the gastrointestinal tract. The mean plasma level of chlorhexidine gluconate reached a peak of 0.206μg/g in humans 30 minutes after they ingested a 300-mg dose of the drug. Detectable levels of chlorhexidine gluconate were not present in the plasma of these subjects 12 hours after the compound was administered. Excretion of chlorhexidine gluconate occurred primarily through the feces (~90%). Less than 1% of the chlorhexidine gluconate ingested by these subjects was excreted in the urine. Reference ID: 3246401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATION Peridex is indicated for use between dental visits as part of a professional program for the treatment of gingivitis as characterized by redness and swelling of the gingivae, including gingival bleeding upon probing. Peridex has not been tested among patients with acute necrotizing ulcerative gingivitis (ANUG). For patients having coexisting gingivitis and periodontitis, see PRECAUTIONS. CONTRAINDICATIONS Peridex should not be used by persons who are known to be hypersensitive to chlorhexidine gluconate or other formula ingredients. WARNINGS The effect of Peridex on periodontitis has not been determined. An increase in supragingival calculus was noted in clinical testing in Peridex users compared with control users. It is not known if Peridex use results in an increase in subgingival calculus. Calculus deposits should be removed by a dental prophylaxis at intervals not greater than six months. Anaphylaxis, as well as serious allergic reactions, have been reported during postmarketing use with dental products containing chlorhexidine. (SEE CONTRAINDICATIONS). PRECAUTIONS GENERAL 1. For patients having coexisting gingivitis and periodontitis, the presence or absence of gingival inflammation following treatment with Peridex should not be used as a major indicator of underlying periodontitis. 2. Peridex can cause staining of oral surfaces, such as tooth surfaces, restorations, and the dorsum of the tongue. Not all patients will experience a visually significant increase in toothstaining. In clinical testing, 56% of Peridex users exhibited a measurable increase in facial anterior stain, compared to 35% of control users after six months; 15% of Peridex users developed what was judged to be heavy stain, compared to 1% of control users after six months. Stain will be more pronounced in patients who have heavier accumulations of unremoved plaque. Stain resulting from use of Peridex does not adversely affect health of the gingivae or other oral tissues. Stain can be removed from most tooth surfaces by conventional professional prophylactic techniques. Additional time may be required to complete the prophylaxis. Discretion should be used when prescribing to patients with anterior facial restorations with rough surfaces or margins. If natural stain cannot be removed from these surfaces by a dental prophylaxis, patients should be excluded from Peridex treatment if permanent discoloration is unacceptable. Stain in these areas may be difficult to remove by dental prophylaxis and on rare occasions may necessitate replacement of these restorations. Reference ID: 3246401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Some patients may experience an alteration in taste perception while undergoing treatment with Peridex. Rare instances of permanent taste alteration following Peridex use have been reported via post-marketing product surveillance. PREGNANCY: TERATOGENIC EFFECTS Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at chlorhexidine gluconate doses up to 300mg/kg/day and 40mg/kg/day, respectively, and have not revealed evidence of harm to fetus. However, adequate and well-controlled studies in pregnant women have not been done. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. NURSING MOTHERS: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Peridex is administered to nursing women. In parturition and lactation studies with rats, no evidence of impaired parturition or of toxic effects to suckling pups was observed when chlorhexidine gluconate was administered to dams at doses that were over 100 times greater than that which would result from a person's ingesting 30ml (2 capfuls) of Peridex per day. PEDIATRIC USE: Clinical effectiveness and safety of Peridex have not been established in children under the age of 18. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: In a drinking water study in rats, carcinogenic effects were not observed at doses up to 38mg/kg/day. Mutagenic effects were not observed in two mammalian in vivo mutagenesis studies with chlorhexidine gluconate. The highest doses of chlorhexidine used in a mouse dominant-lethal assay and a hamster cytogenetics test were 1000mg/kg/day and 250mg/kg/day, respectively. No evidence of impaired fertility was observed in rats at doses up to 100mg/kg/day. ADVERSE REACTIONS The most common side effects associated with chlorhexidine gluconate oral rinses are: 1) an increase in staining of teeth and other oral surfaces; 2) an increase in calculus formation; and 3) an alteration in taste perception, see WARNINGS and PRECAUTIONS. Oral irritation and local allergy-type symptoms have been spontaneously reported as side effects associated with use of chlorhexidine gluconate rinse. The following oral mucosal side effects were reported during placebo-controlled adult clinical trials: aphthous ulcer, grossly obvious gingivitis, trauma, ulceration, erythema, desquamation, coated tongue, keratinization, geographic tongue, mucocele, and short frenum. Each occurred at a frequency of less than 1.0%. Among post marketing reports, the most frequently reported oral mucosal symptoms associated with Peridex are stomatitis, gingivitis, glossitis, ulcer, dry mouth, hypesthesia, glossal edema, and paresthesia. Minor irritation and superficial desquamation of the oral mucosa have been Reference ID: 3246401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda noted in patients using Peridex. There have been cases of parotid gland swelling and inflammation of the salivary glands (sialadenitis) reported in patients using Peridex. OVERDOSAGE Ingestion of 1 or 2 ounces of Peridex by a small child (~10 kg body weight) might result in gastric distress, including nausea, or signs of alcohol intoxication. Medical attention should be sought if more than 4 ounces of Peridex is ingested by a small child or if signs of alcohol intoxication develop. DOSAGE AND ADMINISTRATION Peridex therapy should be initiated directly following a dental prophylaxis. Patients using Peridex should be reevaluated and given a thorough prophylaxis at intervals no longer than six months. Recommended use is twice daily oral rinsing for 30 seconds, morning and evening after toothbrushing. Usual dosage is 15ml (marked in cap) of undiluted Peridex. Patients should be instructed to not rinse with water or other mouthwashes, brush teeth or eat immediately after using Peridex. Peridex is not intended for ingestion and should be expectorated after rinsing. HOW SUPPLIED Peridex is supplied as a blue liquid in the following sizes: 0.5 fluid ounce (15 ml) (NDC 48878-0620-4) amber plastic bottle with child resistant dispensing closure 4 fluid ounce (118 ml) (NDC 48878-0620-3) amber plastic bottles with child resistant dispensing closure 16 fluid ounce or 1 pint (473ml) (NDC 48878-0620-1) amber plastic bottles with child- resistant dispensing closure 64 fluid ounce (1893 ml) (NDC 48878-0620-2) white plastic bottle with pump dispensing closure STORE at 20°C to 25°C (68°F to 77°F ), excursions permitted to 15°C to 30°C °F (59°F to 86°F) [See USP controlled room temperature]. Rx only Keep out of reach of children Reference ID: 3246401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What to expect when using Peridex™ Chlorhexidine Gluconate 0.12% Oral Rinse Your dentist has prescribed Peridex™ Chlorhexidine Gluconate 0.12% Oral Rinse to treat your gingivitis, to help reduce the redness and swelling of your gums, and also to help you control any gum bleeding. Use Peridex oral rinse regularly, as directed by your dentist, in addition to daily brushing. Spit out after use. Peridex oral rinse should not be swallowed. If you develop allergic symptoms such as skin rash, itch, generalized swelling, breathing difficulties, light headedness, rapid heart rate, upset stomach or diarrhea, seek medical attention immediately. Peridex oral rinse should not be used by persons who have a sensitivity to it or its components. Peridex oral rinse may cause some tooth discoloration or increase in tartar (calculus) formation, particularly in areas where stain and tartar usually form. It is important to see your dentist for removal of any stain or tartar at least every six months or more frequently if your dentist advises. • Both stain and tartar can be removed by your dentist or hygienist. Peridex oral rinse may cause permanent discoloration of some front-tooth fillings. • To minimize discoloration, you should brush and floss daily, emphasizing areas which begin to discolor. • Peridex oral rinse may taste bitter to some patients and can affect how foods and beverages taste. This will become less noticeable in most cases with continued use of Peridex oral rinse. • To avoid taste interference, rinse with Peridex oral rinse after meals. Do not rinse with water or other mouthwashes immediately after rinsing with Peridex oral rinse. If you have any questions or comments about Peridex oral rinse, contact your dentist or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. STORE at 20°C to 25°C (68°F to 77°F ), excursions permitted to 15°C to 30°C °F (59°F to 86°F) [See USP controlled room temperature] Revised: January/2013 Made in U.S.A. for: 3M ESPE Dental Products 2510 Conway Avenue St. Paul, MN 55144-1000 USA © 3M 2013 Reference ID: 3246401 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.736414	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019028s020lbl.pdf', 'application_number': 19028, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,419	---------- PERIDEX - chlorhexidine gluconate mouthwash 3M Peridex™ (CHLORHEXIDINE GLUCONATE 0.12%) ORAL RINSE DESCRIPTION Peridex is an oral rinse containing 0.12% chlorhexidine gluconate (1, 11-hexamethylene bis [5-(p-chlorophenyl) biguanide] di-D-gluconate) in a base containing water, 11.6% alcohol, glycerin, PEG-40 sorbitan diisostearate, flavor, sodium saccharin, and FD&C Blue No. 1. Peridex oral rinse is a near-neutral solution (pH range 5-7). Chlorhexidine gluconate is a salt of chlorhexidine and gluconic acid. Its chemical structure is: chemical structure CLINICAL PHARMACOLOGY Peridex provides antimicrobial activity during oral rinsing. The clinical significance of Peridex's antimicrobial activities is not clear. Microbiological sampling of plaque has shown a general reduction of counts of certain assayed bacteria, both aerobic and anaerobic, ranging from 54-97% through six months use. Use of Peridex oral rinse in a six month clinical study did not result in any significant changes in bacteria resistance, overgrowth of potentially opportunistic organisms or other adverse changes in the oral microbial ecosystem. Three months after Peridex use was discontinued, the number of bacteria in plaque had returned to baseline levels and resistance of plaque bacteria to chlorhexidine gluconate was equal to that at baseline. PHARMACOKINETICS Pharmacokinetic studies with Peridex indicate approximately 30% of the active ingredient, chlorhexidine gluconate, is retained in the oral cavity following rinsing. This retained drug is slowly released into the oral fluids. Studies conducted on human subjects and animals demonstrate chlorhexidine gluconate is poorly absorbed from the gastrointestinal tract. The mean plasma level of chlorhexidine gluconate reached a peak of 0.206μg/g in humans 30 minutes after they ingested a 300-mg dose of the drug. Detectable levels of chlorhexidine gluconate were not present in the plasma of these subjects 12 hours after the compound was administered. Excretion of chlorhexidine gluconate occurred primarily through the feces (~90%). Less than 1% of the chlorhexidine gluconate ingested by these subjects was excreted in the urine. Reference ID: 3244028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATION Peridex is indicated for use between dental visits as part of a professional program for the treatment of gingivitis as characterized by redness and swelling of the gingivae, includin g gingival bleeding upon probing. Peridex has not been tested among patients with acute necrotizing ulcerative gingivitis (ANUG). For patients having coexisting gingivitis and periodontitis, see PRECAUTIONS. CONTRAINDICATIONS Peridex should not be used by persons who are known to be hypersensitive to chlorhexidine gluconate or other formula ingredients. WARNINGS The effect of Peridex on periodontitis has not been determined. An increase in supragingival calculus was noted in clinical testing in Peridex users compared with control users. It is not known if Peridex use results in an increase in subgingival calculus. Calculus deposits should be removed by a dental prophylaxis at intervals not greater than six months. Hypersensitivity and generalized allergic reactions have occurred. SEE CONTRAINDICATIONS. PRECAUTIONS GENERAL 1. For patients having coexisting gingivitis and periodontitis, the presence or absence of gingival inflammation following treatment w ith Peridex should not be used as a major indicator of underlying periodontitis. 2. Peridex can cause staining of oral surfaces, such as tooth surfaces, restorations, and the dorsum of the tongue. Not all patients will experience a visually significant increase in toothstaining. In clinical testing, 56% of Peridex users exhibited a measurable increase in facial anterior stain, compared to 35% of control users after six months; 15% of Peridex users developed what was judged to be heavy stain, compared to 1% of control users after six months. Stain wil l be more pronounced in patients who have heavier accumulations of unremoved plaque. Stain resulting from use of Peridex does not adversely affect health of the gingivae or other oral tissues. Stain can be removed from most tooth surface s by conventional professional prophylactic techniques. Additional time may be required to complete the prophylaxis. Discretion should be used when prescrib ing to patients with anterior facial restorations with rough surfaces or margins. If natural stain cannot be removed from these surfaces by a dental prophylaxis, patients should be excluded from Peridex treatment if permanent discolo ration is unacceptable. Stain in these areas may be difficult to remove by dental prophylaxis an d on rare occasions may necessitate replacement of these restorations. Reference ID: 3244028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3. Some patients may experience an alteration in taste perception while undergoing treatment with Peridex. Rare instances of permanent taste alteration following Peridex use have been reported via post-marketing product surveillance. PREGNANCY: TERATOGENIC EFFECTS Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at chlorhexidine gluconate doses up to 300mg/kg/day and 40mg/kg/day, respectively, and have not reveal ed evidence of harm to fetus. However, adequate and well-controlled studies in pregnant women have not been done. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. NURSING MOTHERS: It is not known whether this drug is excreted in human milk . Because many drugs are excreted in human milk, caution should be exercised when Peridex is administered to nursing women. In parturition and lactation studies with rats, no evidence of im paired parturition or of toxic effects to suckling pups was observed when chlorhexidine gluconate was administered to dams at doses that were over 100 times greater than that which would result from a person's ingesting 30ml (2 capfuls) of Peridex per day. PEDIATRIC USE: Clinical effectiveness and safety of Peridex have not been established in children under the age of 18. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: In a drinking water study in rats, carcinogenic effects were not observed at dose s up to 38mg/kg/day. Mutagenic effects were not observed in two mammalian in vivo mutagenesis studies with chlorhexidine glucona te. The highest doses of chlorhexidine used in a mouse dominant-lethal assay and a hamster cytogenetics test were 1000mg/kg/day and 250mg/kg/day, respectively. No evidence of impaired fertility was observed in rats at doses up to 100mg/kg/day. ADVERSE REACTIONS The most common side effects associated with chlorhexidine gluconate oral r inses are: 1) an increase in staining of teeth and other oral surfaces; 2) an increase in calculus formation; and 3) an alteration in taste perception, see WARNINGS and PRECAUTIONS. Oral irritation and local allergy-type symptoms have been spontaneously reported as side effects associated with use of chlorhexidine gluconate rinse. The following oral mucosal side effects were reported during placebo-controlled adult clinical trials: aphthous ulcer, grossly obvious gingivitis, trauma, ulceration, erythema, desquamation, coated tongue, keratinization, geographic tongue, mucoc ele, and short frenum. Each occurred at a frequency of less than 1.0%. Among post marketing reports, the most frequently reported oral mucosal symptoms associated with Peridex a re stomatitis, gingivitis, glossitis, ulcer, dry mouth, hypesthesia, glossal edema, and paresthesia. Minor irritation and superficial desquamation of the oral mucosa have been Reference ID: 3244028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda noted in patients using Peridex. There have been cases of parotid gland swelling and inflammation of the salivary glands (sialadenitis) reported in patients using Peridex. OVERDOSAGE Ingestion of 1 or 2 ounces of Peridex by a small child (~10 kg body weight) might result in gastric distress, including nausea, or signs of alcohol intoxication. Medical attention should be sought if more than 4 ounces of Peridex is ingested by a small child or if signs of alcohol intoxication develop. DOSAGE AND ADMINISTRATION Peridex therapy should be initiated directly following a dental prophylaxis. Patients u sing Peridex should be reevaluated and given a thorough prophylaxis at intervals no longe r than six months. Recommended use is twice daily oral rinsing for 30 seconds, morning and evening after toothbrushing. Usual dosage is 15ml (marked in cap) of undiluted Peridex. Patients should be instructed to not rinse with water or other mouthwashes, brush teeth or eat immediately after using Peridex. Peridex is not intended for ingestion and should be expectorated after rinsing. HOW SUPPLIED Peridex is supplied as a blue liquid in the following sizes: 0.5 fluid ounce (15 ml) (NDC 48878-0620-4) amber plastic bottle with child resistant dispensing closure 4 fluid ounce (118 ml) (NDC 48878-0620-3) amber plastic bottles with child resistant dispensing closure 16 fluid ounce or 1 pint (473ml) (NDC 48878-0620-1) amber plastic bottles with child- resistant dispensing closure 64 fluid ounce (1893 ml) (NDC 48878-0620-2) white plastic bottle with pump dispensing closure STORE ABOVE FREEZING (32°F or 0°C) Rx only Keep out of reach of children Revised: January/2013 Made in USA for: 3M ESPE Dental Products St. Paul, MN 55144-1000 USA © 3M 2013 Reference ID: 3244028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What to expect when using Peridex™ Chlorhexidine Gluconate 0.12% Oral Rinse Your dentist has prescribed Peridex™ Chlorhexidine Gluconate 0.12% Oral Rinse to treat your gingivitis, to help reduce the redness and swelling of your gums, and also to help you control any gum bleeding. Use Peridex oral rinse regularly, as directed by your dentist, in addition to daily brushing. Spit out after use. Peridex oral rinse should not be swallowed. Peridex oral rinse may cause some tooth discoloration or increase in tartar (calculus) formation, particularly in areas where stain and tartar usually form. It is important to see your dentist for removal of any stain or tartar at least every six months or more frequently if your dentist advises. • Both stain and tartar can be removed by your dentist or hygienist. Peridex oral rinse may cause permanent discoloration of some front-tooth fillings. • To minimize discoloration, you should brush and floss daily, emphasizing areas which begin to discolor. • Local hypersensitivity and sometimes generalized allergic reactions have also been reported. Peridex oral rinse should not be used by persons who have a sensitivity to it or its components. • Peridex oral rinse may taste bitter to some patients and can affect how foods and beverages taste. This will become less noticeable in most cases with continued use of Peridex oral rinse. • To avoid taste interference, rinse with Peridex oral rinse after meals. Do not rinse with water or other mouthwashes immediately after rinsing with Peridex oral rinse. If you have any questions or comments about Peridex oral rinse, contact your dentist or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. STORE ABOVE FREEZING (32°F or 0°C) Made in U.S.A. for: 3M ESPE Dental Products St. Paul, MN 55144-1000 Reference ID: 3244028 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.821815	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019028s022lbl.pdf', 'application_number': 19028, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,420	Rx only DILAUDID-HP® INJECTION 10 mg/mL (hydromorphone hydrochloride) CII WARNING: DILAUDID-HP® (HIGH POTENCY) IS A HIGHLY CONCENTRATED SOLUTION OF HYDROMORPHONE, A POTENT SCHEDULE II CONTROLLED OPIOID AGONIST, INTENDED FOR USE IN OPIOID-TOLERANT PATIENTS. DO NOT CONFUSE DILAUDID-HP WITH STANDARD PARENTERAL FORMULATIONS OF DILAUDID OR OTHER OPIOIDS. OVERDOSE AND DEATH COULD RESULT. SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE, OXYMORPHONE, OXYCODONE, FENTANYL AND METHADONE, HAVE THE HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING RESPIRATORY DEPRESSION. ALCOHOL, OTHER OPIOIDS AND CENTRAL NERVOUS SYSTEM DEPRESSANTS (SEDATIVE-HYPNOTICS) POTENTIATE THE RESPIRATORY DEPRESSANT EFFECTS OF HYDROMORPHONE, INCREASING THE RISK OF RESPIRATORY DEPRESSION THAT MIGHT RESULT IN DEATH. DESCRIPTION: DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid analgesic. HIGH POTENCY DILAUDID is available in AMBER ampules or single dose vials for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each 1 mL of sterile solution contains 10 mg hydromorphone hydrochloride with 0.2% sodium citrate, and 0.2% citric acid solution. It is also available as lyophilized DILAUDID for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each single dose vial contains 250 mg sterile, lyophilized hydromorphone HCl to be reconstituted with 25 mL of Sterile Water for Injection USP to provide a solution containing 10 mg/mL. The chemical name of DILAUDID (hydromorphone hydrochloride) is 4,5α-epoxy-3-hydroxy- 17-methylmorphinan-6-one hydrochloride. The structural formula is: M.W. 321.8 CLINICAL PHARMACOLOGY: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 2 Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness. Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. Many of the effects described below are common to the class of mu-opioid analgesics, which includes morphine, oxycodone, hydrocodone, codeine, and fentanyl. In some instances, data may not exist to demonstrate that DILAUDID-HP possesses similar or different effects than those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that DILAUDID-HP would possess these effects. Central Nervous System: . The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects by combining with these receptors. Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla. Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension. Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than mioisis may be seen with hypoxia in the setting of DILAUDID overdose. Gastrointestinal Tract and Other Smooth Muscle: Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Cardiovascular System: Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of histamine, or both . Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes. Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive. PHARMACOKINETICS AND METABOLISM: Distribution: At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 (32%) liters. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 3 Metabolism: Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6- hydroxy reduction metabolites. Elimination: Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours. Special Populations: Hepatic Impairment: After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR Tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4 fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at a lower dose and closely monitored during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE and ADMINISTRATION). Renal impairment: After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR Tablets), mean exposure to hydromorphone ( Cmax and AUC0-48) is increased in patients with impaired renal function by 2-fold, in moderate (CLcr = 40 - 60 mL/min) and 3-fold in severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients with severe renal impairment should be even lower. Patients with renal impairment should be closely monitored during dose titration. Use of oral liquid is recommended to adjust the dose (see DOSAGE and ADMINISTRATION). Pediatrics: Pharmacokinetics of hydromorphone have not been evaluated in children. Geriatric: Age has no effect on the pharmacokinetics of hydromorphone. Gender: Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may not be clinically relevant. Pregnancy and nursing mothers: Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, and may cause respiratory compromise in newborns when administered during labor or delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 4 INDICATIONS AND USAGE: DILAUDID-HP is indicated for the relief of moderate-to-severe pain in opioid-tolerant patients who require larger than usual doses of opioids to provide adequate pain relief. Because DILAUDID- HP contains 10 mg of hydromorphone hydrochloride per mL, a smaller injection volume can be used than with other parenteral opioid formulations. Discomfort associated with the intramuscular or subcutaneous injection of an unusually large volume of solution can therefore be avoided. CONTRAINDICATIONS: DILAUDID-HP is contraindicated in: patients who are not already receiving large amounts of parenteral opioids, patients with known hypersensitivity to hydromorphone, patients with respiratory depression in the absence of resuscitative equipment, and in patients with status asthmaticus. DILAUDID-HP is also contraindicated for use in obstetrical analgesia. WARNINGS - Respiratory Depression: Respiratory depression is the chief hazard of DILAUDID-HP. Respiratory depression occurs most frequently in overdose situations, in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. DILAUDID-HP should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. DILAUDID-HP contains hydromorphone, which is a potent Schedule II, controlled opioid agonist. Schedule II opioid agonists, including morphine, oxycodone, oxymorphone, fentanyl and methadone, have the highest potential for abuse and risk of fatal respiratory depression. Alcohol, other opioids and central nervous system depressants (sedative-hypnotics) potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death. Misuse, Abuse, and Diversion of Opioids Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. DILAUDUD HP can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing DILAUDID in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients, however, they will require intensive monitoring for signs of abuse. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 5 Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Hydromorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Neonatal Withdrawal Syndrome: Infants born to mothers physically dependent on DILAUDID-HP will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see DRUG ABUSE AND DEPENDENCE). Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of DILAUDID- HP with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including DILAUDID-HP may produce effects on pupillary response and consciousness which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries. Hypotensive Effect: Opioid analgesics, including DILAUDID-HP, may cause severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics (see PRECAUTIONS-Drug Interactions). DILAUDID-HP may produce orthostatic hypotension in ambulatory patients. DILAUDID-HP should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Sulfites: Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS: General: Because of its high concentration, the delivery of precise doses of DILAUDID-HP may be difficult if low doses of hydromorphone are required. Therefore, DILAUDID-HP should be used only if the amount of hydromorphone required can be delivered accurately with this formulation. Special Risk Patients: DILAUDUD HP should be given with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens; or kyphoscoliosis, or following gastrointestinal surgery. In the case of DILAUDID-HP, however, the patient is presumed to be receiving an opioid to which he or she exhibits tolerance and the initial dose of DILAUDID-HP selected should be estimated based on the relative potency of hydromorphone and the opioid previously used by the patient. (see DOSAGE AND ADMINISTRATION). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 6 The administration of opioid analgesics including DILAUDID-HP may obscure the diagnosis or clinical course in patients with acute abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders. Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration at very high doses is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus. Use in Drug and Alcohol Dependent Patients : DILAUDID-HP should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID-HP in combination with other CNS depressant drugs can result in serious risk to the patient. Hydromorphone is an opioid with no approved use in the management of addictive disorders. Use in Ambulatory Patients: DILAUDID HP may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery). Patients should be cautioned accordingly. DILAUDID may produce orthostatic hypotension in ambulatory patients. Use in Biliary Tract Disease: Opioid analgesics, including DILAUDID-HP, should also be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids used regularly should not be abruptly discontinued. Drug Interactions Drug Interactions with other CNS Depressants: The concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Opioid analgesics, including DILAUDID-HP, may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 7 Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients. Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies have been conducted in animals. Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay, or the human lymphocytes chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse micronucleus assay. No effects on fertility, reproductive performance, or reproductive organ morphology were observed in male or female rats given oral doses up to 7 mg/kg/day which is equivalent to and 3-fold higher than the human dose of DILAUDID HP when substituted for ORAL LIQUID or 8mg TABLET, respectively, on a body surface area basis. PREGNANCY-PREGNANCY CATEGORY C: No effects on teratogenicity or embryotoxicity were observed in female rats given oral doses up to 7 mg/kg/day which is equivalent to and 3-fold higher than the human dose of DILAUDID HP, on a body surface area basis. Hydromorphone produced skull malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg during the peak of organogenesis (gestation days 8-9). The skull malformations were observed at doses approximately 2-fold and 7-fold higher than the human dose of DILAUDID HP when substituted for ORAL LIQUID or 8mg TABLET, respectively, on a body surface area basis. There are no adequate and well-controlled studies of DILAUDID in pregnant women. Hydromorphone crosses the placenta, resulting in fetal exposures. DILAUDID HP should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND DEPENDENCE). Nonteratogenic effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital. Labor and Delivery: DILAUDID-HP is contraindicated in Labor and Delivery (see CONTRAINDICATIONS). Nursing Mothers: Low levels of opioid analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving DILAUDID-HP since it, and other drugs in this class, may be excreted in the milk. Pediatric Use: Safety and effectiveness have not been established. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 8 Geriatric Use: Clinical studies of DILAUDID did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see PRECAUTIONS). ADVERSE REACTIONS: The major hazards of DILAUDID-HP include respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred. The most frequently observed adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Adverse Reactions: General and CNS:, Weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity, paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and disorientation, visual disturbances, insomnia, increased intracranial pressure Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension Respiratory: Bronchospasm and laryngospasm Gastrointestinal: Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps taste alterations Genitourinary: Urinary retention or hesitancy, antidiuretic effects Dermatologic: Urticaria, other skin rashes, wheal and flare over the vein with intravenous injection, diaphoresis Other: In clinical trials, neither local tissue irritation nor induration was observed at the site of subcutaneous injection of DILAUDID-HP; pain at the injection site was rarely observed. However, local irritation and induration have been seen following parenteral injection of other opioid drug products. OVERDOSAGE: Serious overdosage with DILAUDID-HP is characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac arrest and death may occur. In the treatment of overdosage, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 9 The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to DILAUDID-HP. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected to be physically dependent on DILAUDID-HP. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Since the duration of action of DILAUDID-HP may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. Apply other supportive measures when indicated. . DOSAGE AND ADMINISTRATION: Parenteral: DILAUDID-HP SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. DILAUDID-HP is indicated for relief of moderate-to-severe pain in opioid-tolerant patients. Thus, these patients will already have been treated with other opioid analgesics. If the patient is being changed from regular DILAUDID to DILAUDID- HP, similar doses should be used, depending on the patient's clinical response to the drug. If DILAUDID-HP is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of DILAUDID-HP (hydromorphone hydrochloride). Patients with hepatic and renal impairment should be started on a lower starting dose (See CLINICAL PHARMAOCOLGY: PHARMCOKINETICS and METABOLISM). The dosage of DILAUDID-HP should be individualized for any given patient, since adverse events can occur at doses that may not provide complete freedom from pain Safe and effective administration of opioid analgesics to patients with acute or chronic pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, etiology, and pathophysiology) as well as the concurrent medical status of the patient will affect selection of the starting dosage. STRONG ANALGESICS AND STRUCTURALLY RELATED DRUGS USED IN THE TREATMENT OF CANCER PAIN * IM OR SC ADMINISTRATION Nonproprietary (Trade) Names Dose, mg Equianalgesic to 10 mg of IM Morphine† Morphine sulfate 10 Hydromorphone (DILAUDID) hydrochloride 1.3 Oxymorphone (Numorphan) hydrochloride 1.1 Nalbuphine (Nubain) hydrochloride 12 Levorphanol (Levo-Dromoran) tartrate 2.3 Butorphanol (Stadol) tartrate 1.5-2.5 Pentazocine (Talwin) lactate or hydrochloride 60 Meperidine, pethidine (Demerol) hydrochloride 80 Methadone (Dolophine) hydrochloride 10 * From Beaver WT Management of cancer pain with parenteral medication. J. Am. Med. Assoc. 244:2653-2657 (1980). † (In terms of the area under the analgesic time-effect curve.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 10 In open clinical trials with DILAUDID-HP in patients with terminal cancer, doses ranged from 1-14 mg subcutaneously or intramuscularly; one patient received 30 mg subcutaneously on two occasions. In these trials, both subcutaneous and intramuscular injections of DILAUDID-HP were well-tolerated, with minimal pain and/or burning at the injection site. Mild erythema was rarely noted after intramuscular injection. There was no induration after either intramuscular or subcutaneous administration of DILAUDID-HP. Subcutaneous injections of DILAUDID-HP were particularly well accepted when administered with a short, 30 gauge needle. Experience with administration of DILAUDID-HP by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes. The intravenous route is usually painless. A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in DILAUDID-HP ampules. No loss of potency has been demonstrated. DILAUDID injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions. 500 mg/50 mL Vial : To use this single dose presentation, do not penetrate the stopper with a syringe. Instead, remove both the aluminum flipseal and rubber stopper in a suitable work area such as under a laminar flow hood (or equivalent clean air compounding area). The contents may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner. CAUTION: The packaging (vial stopper) of this product contains rubber latex which may cause allergic reactions. Reconstitution of sterile lyophilized DILAUDID- HP 250mg: Reconstitute immediately prior to use with 25 mL of Sterile Water for Injection USP to provide a sterile solution containing 10 mg/mL. DRUG ABUSE AND DEPENDENCE: DILAUDIDHP contains hydromorphone, a Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine, oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion. Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage, but it may occur after as little as a week of opioid use. Physical dependence and tolerance are separate and distinct from abuse and addiction. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 11 Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with, forging or counterfeiting prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since DILAUDID may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. DILAUDID-HP is intended for parenteral use only under the direct supervision of an appropriately licensed health care provider. Misuse or abuse of DILAUDID-HP poses a risk of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. SAFETY AND HANDLING INSTRUCTIONS: DILAUDID-HP poses little risk of direct exposure to health care personnel and should be handled and disposed of prudently in accordance with hospital or institutional policy. Patients and their families should be instructed to flush any DILAUDID-HP that is no longer needed. Access to abusable drugs such as DILAUDID-HP presents an occupational hazard for addiction in the health care industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect health care workers. Implementation of more effective accounting procedures and measures to restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-administration by health care providers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-012 Page 12 HOW SUPPLIED: DILAUDID-HP amber ampules and single dose vials contain 10 mg hydromorphone hydrochloride per mL with 0.2% sodium citrate and 0.2% citric acid solution. No added preservative. NOTE: DILAUDID-HP ampules are amber in color. The lyophilized DILAUDID- HP Single Dose Vial contains 250 mg of sterile, lyophilized hydromorphone HCl. HIGH POTENCY: 10 mg/1 mL * 50 mg/5 mL 500 mg/50 mL lyophilized 250 mg Box of 10 ampules Box of 10 ampules Single dose vial Single Dose Vial NDC 0074-2453-11 NDC 0074-2453-27 NDC 0074-2453-51 NDC 0074-2455-31 * FOR USE IN THE PREPARATION OF LARGE VOLUME PARENTERAL SOLUTIONS STORAGE: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Protect from light. A Schedule CII Narcotic. DEA Order Form Required. © Abbott All rights reserved. Revised: NEW NEW This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:12.925687	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019034s012lbl.pdf', 'application_number': 19034, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,417	NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 4 Baxter OSMITROL Injection (Mannitol Injection, USP) in AVIVA Plastic Container For Therapeutic Use Only Description Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. Composition, osmolarity, and pH are shown in Table 1. Composition Table 1 Size (mL) Mannitol, USP (g/L) Osmolarity (mOsmol/L) (calc) pH 5% OSMITROL Injection (5% Mannitol Injection, USP) 1000 50 274 5.5 (4.5 TO 7.0) 500 10% OSMITROL Injection (10% Mannitol Injection, USP) 1000 100 549 5.5 (4.5 TO 7.0) 15% OSMITROL Injection (15% Mannitol Injection, USP) 500 150 823 5.5 (4.5 TO 7.0) 250 20% OSMITROL Injection (20% Mannitol Injection, USP) 500 200 1098 5.5 (4.5 TO 7.0) Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L. Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 5 Mannitol The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for the attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not secreted by the tubule, and is pharmacologically inert. Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 6 and chloride by elevating the osmolarity of the glomerular filtrate. This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure. Indications and Usage Osmitrol Injection (Mannitol Injection, USP) is indicated for: The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established; The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass; The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means, and promoting the urinary excretion of toxic substances. Contraindications Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with: Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal damage or dysfunction after institution of mannitol therapy, including increasing oliguria and azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy. Warnings In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and Administration). A second test dose may be tried if there is an inadequate response, but no more than two test doses should be attempted. The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration. If urine output continues to decline during mannitol infusion, the patient’s clinical status should be closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart failure. Excessive loss of water and electrolytes may lead to serious imbalances. With continued administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte measurements, including sodium and potassium, are therefore, of vital importance in monitoring the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 7 infusion of mannitol. Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during mannitol infusion. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. The cardiovascular status of the patient should be carefully evaluated before rapidly administrating mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia. By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolemia. Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool to room temperature before reinspection for crystals. Administer intravenously using sterile, filter- type administration set. Laboratory Tests Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 8 The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring. Drug Interaction Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol Injection (Mannitol Injection, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also not known whether mannitol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. Usage in Children Dosage requirements for patients 12 years of age and under have not been established. Geriatric Use Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 9 to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Extensive use of mannitol over the last several decades has produced recorded adverse events, in a variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions have occurred with any great frequency nor with any security in attributing them to mannitol. The inability to clearly exclude the drug related nature of such events in these isolated reports prompts the necessity to list the reactions that have been observed in patients during or following mannitol infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension, tachycardia, fever and angina-like chest pains. Of far greater clinical significance is a variety of events that are related to inappropriate recognition and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner. Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or aggravate preexisting hyponatremia. If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred vision, convulsions and congestive cardiac failure. These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of degree of renal failure with a test dose response to mannitol when indicated; evaluation of hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration; and evaluation of renal, cardiac and pulmonary function at the onset of therapy. Dosage and Administration Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion. The total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 10 and dosage is only a general guide to therapy. Parenteral dug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20% solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if there is an inadequate response, the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will depend upon the fluid requirements of the patient. Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20% solution. Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a prompt and maximal effect. When used preoperatively the dose should be given one to one and one- half hours before surgery to achieve maximal reduction of intraocular pressure before operation. Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a satisfactory reduction in intracranial pressure. Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15% or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary output of the patient. Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of dosage. All injections in AVIVA containers are intended for intravenous administration using sterile equipment. The use of supplemental additive medication is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 11 How Supplied Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows: Code Size (mL) NDC Product Name 6E5604 1000 0338-6300-04 5% Osmitrol Injection (5% Mannitol Injection, USP) 6E5613 6E5614 500 1000 0338-6301-03 0338-6301-04 10% Osmitrol Injection (10% Mannitol Injection, USP) 6E5623 500 0338-6302-03 15% Osmitrol Injection (15% Mannitol Injection, USP) 6E5632 6E5633 250 500 0338-6303-02 0338-6303-03 20% Osmitrol Injection (20% Osmitrol Injection) Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 12 ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 13 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 14 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 15 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 16 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 17 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 18 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 19 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 20 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 21 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 22 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 23 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 24 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 25 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). c * D-Glucopyranose monohydrate Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 26 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 27 electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 28 Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum amorality and possible hemorrhage. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 29 reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasations, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size NDC 6E2073 500 mL NDC 0338-6306-03 6E2074 1000 mL NDC 0338-6306-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 30 To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 31 All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 32 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2·2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 250 500 Lactated Ringer’s Injection, USP 1000 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 33 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the treatment of lactic acidosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 34 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Test CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH EVALUATION. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's Injection, USP. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 35 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis; periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of infection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 36 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 37 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 38 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 39 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 40 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 41 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 42 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 43 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 44 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 45 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 46 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 47 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 48 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 49 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 50 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 51 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 52 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 53 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 54 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 55 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 56 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 57 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 58 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 59 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA Plastic Container Description Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Lactate (C3H5NaO3) Osmolarity (mOsmol/L) (calc) pH Sodium Lactate Caloric Content (kcal/L) 500 Sodium Lactate Injection, USP (M/6 Sodium Lactate) 1000 18.7 334 6.5 (6.0 to 7.3) 167 167 54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 60 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications None known Warnings Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result in sodium retention. Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis. Precautions General This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 61 Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium Lactate) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Lactate Injection, USP (M/6 Sodium Lactate). Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6 Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 62 Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 63 How Supplied Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E1803 500 0338-6311-03 6E1804 1000 0338-6311-04 EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 64 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 65 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 66 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 67 edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 68 Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 69 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 70 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 71 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 72 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 73 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 74 Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 75 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 76 Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 77 Baxter Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no antimicrobial agents. The pH is 4.0 (3.5 to 6.5). c D-Glucopyranose monohydrate Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium, 4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 78 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 79 Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5% Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is administered to a nursing woman. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 80 Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of ringer's and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 81 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2064 1000 NDC 0338-6313-04 6E2063 500 NDC 0338-6313-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 82 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter Healthcare International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 83 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 84 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 85 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 86 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 87 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 88 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 89 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 90 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 91 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 92 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 93 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 94 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 95 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 96 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 97 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 98 Clinical Pharmacology PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 99 In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 100 Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 101 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2534 1000 NDC 0338-6316-04 6E2533 500 NDC 0338-6316-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 102 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 103 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 lcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 104 Clinical Pharmacology PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 105 overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 106 A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elkerly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 107 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2544 1000 NDC 0338-6317-04 6E2543 500 NDC 0338-6317-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 108 To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 109 Baxter PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 110 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 111 PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 112 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 113 selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 114 6E2573 500 NDC 0338-6318-03 6E2574 1000 NDC 0338-6318-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 115 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 116 Baxter PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate (C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 117 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 118 administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium ions may result in sodium or potassium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 119 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 120 In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 121 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2564 NDC 0338-6319-04 500 6E2563 NDC 0338-6319-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 122 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 123 Baxter PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl); 89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 124 PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 125 Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA- LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 126 Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 127 Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2504 1000 NDC 0338-6320-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 128 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 129 Baxter PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 130 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 131 The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 132 Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 133 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2584 NDC 0338-6321-04 500 6E2583 NDC 0338-6321-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 134 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 135 XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 136 Baxter 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and 12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq chloride, 23 mEq lactate and 3 mEq phosphate as HPO4 =. The osmolarity is 348 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 137 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 138 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not administer simultaneously with blood. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 139 Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemmorhage. Geriatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 140 Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 141 How Supplied 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2102 250 NDC 0338-6322-02 6E2103 500 NDC 0338-6322-03 6E2104 1000 NDC 0338-6322-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 142 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 143 Baxter Potassium Chloride in 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. HO O OH • H O OH OH HO 2 * D-Glucose monohydrate Composition (g/L) Ionic Concentration (mEq/L) Table 1 Potassium Chloride in 5% Dextrose Injection, USP mEq Potassium Size (mL) *Dextrose Hydrous, USP Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Potassium Chloride Caloric Content (kcal/L) 10 mEq 1000 50 0.75 272 4.5 (3.5 to 6.5) 10 10 170 20 mEq 1000 50 1.5 293 4.5 (3.5 to 6.5) 20 20 170 30 mEq 1000 50 2.24 312 4.5 (3.5 to 6.5) 30 30 170 40 mEq 1000 20 mEq 500 50 3 333 4.5 (3.5 to 6.5) 40 40 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 144 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwarp is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not administer simultaneously with blood. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 145 The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose Injection, USP may result in potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose Injection, USP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 146 Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 147 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1124 1000 0338-6323-04 10 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1134 1000 0338-6324-04 20 mEq Potassium Chloride in 5% Dextrose Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 148 6E1174 1000 0338-6325-04 30 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1264 1000 0338-6326-04 40 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1263 500 0338-6326-03 20 mEq Potassium Chloride in 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 149 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 150 Baxter Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid and electrolyte replenishment in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (Calc.) pH Sodium Potassium Chloride 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 1.5 348 5.5 (3.5 to 6.5) 154 20 174 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 3 388 5.5 (3.5 to 6.5) 154 40 194 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 151 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride Injection, USP may result in sodium or potassium retention. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 152 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 153 Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Geriatric Use Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 154 Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1764 1000 0338-6327-04 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 6E1984 1000 0338-6328-04 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C (104º F) does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 155 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 156 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 157 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 158 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 159 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 160 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 161 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 162 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 163 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 164 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 165 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 166 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 167 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 168 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 169 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 170 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 171 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 172 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 173 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 174 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 175 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 176 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 177 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 178 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 179 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 180 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 181 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 182 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 183 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 184 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 185 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 186 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 187 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 188 Baxter 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate, and 15 mEq phosphate as HPO4 =. The osmolarity is 402 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 189 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen, and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 190 dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overloading causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 191 Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION (MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING MOTHER. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 192 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2112 250 NDC 0338-6338-02 6E2113 500 NDC 0338-6338-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 193 6E2114 1000 NDC 0338-6338-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 194 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 195 Baxter 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container Description 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 size (mL) Sodium Chloride USP (NaCl) Sodium Chloride Osmolarity (mOsmol/L) (calc) pH 3% Sodium Chloride Injection, USP 500 30 513 513 1027 5.5 (4.5 to 7.0) 5% Sodium Chloride Injection, USP 500 50 856 856 1711 5.5 (4.5 to 7.0) Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 196 Clinical Pharmacology 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings 3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage. 3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 197 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3% and 5% Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5% Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 198 Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1353 500 0338-6339-03 3% Sodium Chloride Injection, USP 6E1373 500 0338-6340-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 199 Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 200 Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 201 Baxter PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic, hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains 234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 202 PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of hemolysis. The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 203 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 204 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 205 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2524 1000 NDC 0338-6341-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 206 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 207 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Composition (g/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc.) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 208 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Ionic Concentration (mEq/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 ** The chemical structure for Dextrose Hydrous, USP is shown below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 209 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn product. Warnings Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 210 congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the treatment of lactic acidosis. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 211 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly neonates and low birth weight infants. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 212 from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of fall parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC Product Name 6E2224 1000 NDC 0338-6344-04 20 mEq/L Potassium Chloride in Lactated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 213 Ringer’s and 5% Dextrose Injection, USP 6E2244 1000 NDC 0338-6345-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 214 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.363675	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 19022, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,422	NDA 18925/S-007 NDA 19038/S-003 Page 4 Calan (verapamil hydrochloride) For Intravenous Injection DESCRIPTION Calan (verapamil HCl) is a calcium antagonist or slow-channel inhibitor available as a sterile solution for intravenous injection in 5-mg (2 ml) ampules, 5-mg (2 ml) and 10-mg (4 ml) syringes, and 5-mg (2 ml) and 10-mg (4 ml) vials. Each form contains verapamil HCl 2.5 mg/ml and sodium chloride 8.5 mg/ml in water for injection. Hydrochloric acid and/or sodium hydroxide is used for pH adjustment. The pH of the solution is between 4.1 and 6.0. The structural formula of verapamil HCl is given below: Structural Formula C27H38N2O4 · HCl M.W. = 491.08 Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy-α-(1 methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil HCl is not chemically related to other antiarrhythmic drugs. CLINICAL PHARMACOLOGY Mechanism of action: Calan inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of Calan appears to be due to its effect on the slow channel in cells of the cardiac conductile system. Electrical activity through the SA and AV nodes depends, to a significant degree, upon calcium influx through the slow channel. By inhibiting this influx, Calan slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By interrupting reentry at the AV node, Calan can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (WPW) syndrome. Calan has no effect on conduction across accessory bypass tracts. Calan does not alter the normal atrial action potential or intraventricular conduction time but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. In the isolated rabbit heart, concentrations of Calan that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 5 Calan does not induce peripheral arterial spasm. Calan has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Calan does not alter total serum calcium levels. Hemodynamics: Calan reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of Calan is countered by reduction of afterload, and cardiac index is usually not reduced, but in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection. The commonly used intravenous doses of 5-10 mg Calan produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased. Pharmacokinetics: Intravenously administered Calan has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2-5 hours). In healthy men, orally administered Calan undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N- and O-dealkylated products of Calan. Approximately 70% of an administered dose is excreted in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug. INDICATIONS AND USAGE Calan is indicated for the treatment of supraventricular tachyarrhythmias, including: • Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong- Levine [LGL] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to Calan administration. • Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation, except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). In controlled studies in the U.S., about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil HCl. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a fast ventricular rate respond with a decrease in heart rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after verapamil HCl and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. The effect of a single injection lasts for 30–60 minutes when conversion to sinus rhythm does not occur. Because a small fraction (<1.0%) of patients treated with verapamil HCl respond with life- threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation with an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole - see Contraindications and Warnings), the initial use of intravenous verapamil HCl should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see Suggested This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 6 Treatment of Acute Cardiovascular Adverse Reactions). As familiarity with the patient’s response is gained, an office setting may be acceptable. Cardioversion has been used safely and effectively after intravenous Calan. CONTRAINDICATIONS Intravenous verapamil HCl is contraindicated in: 1. Severe hypotension or cardiogenic shock 2. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy) 5. Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction. 6. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered. 7. Ventricular tachycardia. Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pre-therapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. 8. Known hypersensitivity to verapamil HCl WARNINGS CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME (See Dosage and Administration). Hypotension: Intravenous verapamil often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in 5%-10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required pharmacologic treatment (norepinephrine bitartrate IV, metaraminol bitartrate IV, or 10% calcium gluconate IV). All recovered without sequelae. Extreme bradycardia/asystole: Verapamil affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the U.S. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (See Adverse Reactions including suggested treatment of adverse reactions). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 7 Heart failure: When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before Calan is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Concomitant antiarrhythmic therapy: Digitalis: Intravenous verapamil has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia. Procainamide: Intravenous verapamil has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects. Quinidine: Intravenous verapamil has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However a few cases of hypotension have been reported in patients taking oral quinidine who received intravenous verapamil. Caution should therefore be used when employing this combination of drugs. Beta-adrenergic blocking drugs: Intravenous verapamil has been administered to patients receiving oral beta blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility or AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta blockers and intravenous verapamil has resulted in serious adverse reactions (see Contraindications), especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction. Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Heart block: Calan prolongs AV conduction time. While high-degree AV block has not been observed in controlled clinical trials in the U.S., a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed (See Adverse Reactions and Concomitant antiarrhythmic therapy). Hepatic and renal failure: Significant hepatic and renal failure should not increase the effects of a single intravenous dose of Calan but may prolong its duration. Repeated injections of intravenous Calan in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Data on the clearance of verapamil by dialysis are not yet available. Premature ventricular contractions: During conversion to normal sinus rhythm or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil. Similar complexes are seen during This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 8 spontaneous conversion of supraventricular tachycardia and after DC-cardioversion or other pharmacologic therapy. These complexes appear to have no clinical significance. Duchenne’s muscular dystrophy: Intravenous verapamil can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution. Increased intracranial pressure: Intravenous verapamil has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed. PRECAUTIONS Drug interactions: (See Warnings: Concomitant antiarrhythmic therapy) Intravenous verapamil has been used concomitantly with other cardioactive drugs (e.g., digitalis) without evidence of serious negative drug interactions. In rare instances, including when patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil, serious adverse effects have occurred. Concomitant use of verapamil with agents that decrease adrenergic function may result in an exaggerated hypotensive response. Animal studies suggest concomitant use of intravenous verapamil and intravenous dantrolene sodium may result in cardiovascular collapse. The clinical relevance of these findings is unknown. Cimetidine has no effect on intravenous Calan kinetics. As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs. Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 9 Labor and delivery: There have been few controlled studies to determine whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of intravenous Calan in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing mothers: Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric use: Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with intravenous administration in more than 250 patients, about half under 12 months of age and about 25% newborn, indicates that results of treatment are similar to those in adults. However, in rare instances, severe hemodynamic side effects have occurred following the intravenous administration of verapamil in neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients. The most commonly used single doses in patients up to 12 months of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to 0.3 mg/kg of body weight. Most of the patients received the lower dose of 0.1 mg/kg once, but in some cases, the dose was repeated once or twice every 10 to 30 minutes. ADVERSE REACTIONS The following reactions were reported with intravenous verapamil use in controlled U.S. clinical trials involving 324 patients: Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in open clinical trials in more than 7,900 patients was similar. Central nervous system effects: Dizziness (1.2%); headache (1.2%). Although rare, cases of seizures during verapamil injection have been reported. Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). In rare cases of hypersensitivity, broncho/laryngeal spasm accompanied by itch and urticaria has been reported. The following reactions were reported in a few patients: emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, or diaphoresis. Suggested Treatment of Acute Cardiovascular Adverse Reactions* The frequency of these adverse reactions was quite low, and experience with their treatment has been limited. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 10 1. Symptomatic Dopamine HCl IV Intravenous hypotenstion Calcium chloride IV fluids requiring Norepinephrine bitartrate IV Trendelenburg treatment Metaraminol bitartrate IV position Isoproterenol HCl IV 2. Bradycardia, AV Isoproterenol HCl IV Intravenous block, Asystole Calcium chloride IV fluids Norepinephrine bitartrate IV (slow drip) Atropine sulfate IV Cardiac pacing 3. Rapid ventricular DC-cardioversion Intravenous rate (due to (high energy may fluids antegrade con be required) (slow drip) duction in Procainamide IV flutter/fibrilla- Lidocaine HCl IV tion with WPW or LGL syndromes) *Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions (calcium chloride) have been effectively used in treatment of deliberate overdosage with oral verapamil. Clinically significant hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). DOSAGE AND ADMINISTRATION For intravenous use only. CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ECG AND BLOOD PRESSURE MONITORING. The recommended intravenous doses of Calan are as follows: Adult: Initial dose—5-10 mg (0.075-0.15 mg/kg body weight) given as an intravenous bolus. Repeat dose—10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. Older patients—The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. Pediatric: Initial dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) should be administered as an intravenous bolus. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) should be administered as an intravenous bolus. Do not exceed 5 mg. Adverse Proven Effective Supportive Reaction Treatment Treatment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 18925/S-007 NDA 19038/S-003 Page 11 Repeat dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) 30 minutes after the first dose if the initial response is not adequate. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a single dose. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. For stability reasons this product is not recommended for dilution with Sodium Lactate Injection USP in polyvinyl chloride bags. Admixing intravenous Calan with albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided. Calan will precipitate in any solution with a pH above 6.0. HOW SUPPLIED All forms are individually packaged. Size NDC Number Carton Size 5-mg (2 ml) ampule 0025-1853-10 10 5-mg (2 ml) vial 0025-1864-05 5 10-mg (4 ml) vial 0025-1874-05 5 5-mg (2 ml) syringe 0025-1958-05 5 10-mg (4 ml) syringe 0025-1968-05 5 Store at 59° to 86°F (15° to 30°C) and protect from light during storage. Company logo LAB-0421-1.0 Revised October 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.476309	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018925s007,019038s003lbl.pdf', 'application_number': 19038, 'submission_type': 'SUPPL ', 'submission_number': 3}
11,423	CALAN® (verapamil hydrochloride) For Intravenous Injection DESCRIPTION CALAN (verapamil HCl) is a calcium antagonist or slow-channel inhibitor available as a sterile solution for intravenous injection in 5-mg (2 ml) ampules, 5-mg (2 ml) and 10-mg (4 ml) syringes, and 5-mg (2 ml) and 10-mg (4 ml) vials. Each form contains verapamil HCl 2.5 mg/ml and sodium chloride 8.5 mg/ml in water for injection. Hydrochloric acid and/or sodium hydroxide is used for pH adjustment. The pH of the solution is between 4.1 and 6.0. The structural formula of verapamil HCl is given below: structural formula C27H38N2O4 · HCl M.W. = 491.08 Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy α-(1-methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil HCl is not chemically related to other antiarrhythmic drugs. CLINICAL PHARMACOLOGY Mechanism of action: CALAN inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of CALAN appears to be due to its effect on the slow channel in cells of the cardiac conductile system. Electrical activity through the SA and AV nodes depends, to a significant degree, upon calcium influx through the slow channel. By inhibiting this influx, CALAN slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By interrupting reentry at the AV node, CALAN can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (WPW) syndrome. CALAN has no effect on conduction across accessory bypass tracts. CALAN does not alter the normal atrial action potential or intraventricular conduction time but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In the isolated rabbit heart, concentrations of CALAN that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers. CALAN does not induce peripheral arterial spasm. CALAN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. CALAN does not alter total serum calcium levels. Hemodynamics: CALAN reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of CALAN is countered by reduction of afterload, and cardiac index is usually not reduced, but in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection. The commonly used intravenous doses of 5-10 mg CALAN produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased. Pharmacokinetics: Intravenously administered CALAN has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2-5 hours). In healthy men, orally administered CALAN undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N- and O-dealkylated products of CALAN. Approximately 70% of an administered dose is excreted in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug. INDICATIONS AND USAGE CALAN is indicated for the treatment of supraventricular tachyarrhythmias, including: • Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to CALAN administration. • Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation, except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). In controlled studies in the U.S., about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil HCl. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a fast ventricular rate respond with a decrease in heart rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda rhythm is uncommon (about 10%) after verapamil HCl and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. The effect of a single injection lasts for 30–60 minutes when conversion to sinus rhythm does not occur. Because a small fraction (<1.0%) of patients treated with verapamil HCl respond with life- threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation with an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole–—see Contraindications and Warnings), the initial use of intravenous verapamil HCl should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). As familiarity with the patient’s response is gained, an office setting may be acceptable. Cardioversion has been used safely and effectively after intravenous CALAN. CONTRAINDICATIONS Intravenous verapamil HCl is contraindicated in: 1. Severe hypotension or cardiogenic shock 2. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy) 5. Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction. 6. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered. 7. Ventricular tachycardia. Administration of intravenous verapamil to patients with wide- complex ventricular tachycardia (QRS≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. 8. Known hypersensitivity to verapamil HCl WARNINGS CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME. (See Dosage and Administration.) Hypotension: Intravenous verapamil often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in 5%-10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required pharmacologic treatment (norepinephrine bitartrate IV, metaraminol bitartrate IV, or 10% calcium gluconate IV). All recovered without sequelae. Extreme bradycardia/asystole: Verapamil affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the U.S. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. (See Adverse Reactions including suggested treatment of adverse reactions.) Heart failure: When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before CALAN is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Concomitant antiarrhythmic therapy: Digitalis: Intravenous verapamil has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia. Procainamide: Intravenous verapamil has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects. Quinidine: Intravenous verapamil has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However a few cases of hypotension have been reported in patients taking oral quinidine who received intravenous verapamil. Caution should therefore be used when employing this combination of drugs. Beta-adrenergic blocking drugs: Intravenous verapamil has been administered to patients receiving oral beta blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility or AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta blockers and intravenous verapamil has resulted in serious adverse reactions (see Contraindications), especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction. Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Disopyramide: Until data on possible interactions between verapamil and disopyramide are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Heart block: CALAN prolongs AV conduction time. While high-degree AV block has not been observed in controlled clinical trials in the U.S., a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed. (See Adverse Reactions and Concomitant antiarrhythmic therapy.) Hepatic and renal failure: Significant hepatic and renal failure should not increase the effects of a single intravenous dose of CALAN but may prolong its duration. Repeated injections of intravenous CALAN in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Data on the clearance of verapamil by dialysis are not yet available. Premature ventricular contractions: During conversion to normal sinus rhythm or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil. Similar complexes are seen during spontaneous conversion of supraventricular tachycardia and after DC-cardioversion or other pharmacologic therapy. These complexes appear to have no clinical significance. Duchenne’s muscular dystrophy: Intravenous verapamil can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution. Increased intracranial pressure: Intravenous verapamil has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed. PRECAUTIONS Drug interactions: (See Warnings: Concomitant antiarrhythmic therapy.) Intravenous verapamil has been used concomitantly with other cardioactive drugs (e.g., digitalis) without evidence of serious negative drug interactions. In rare instances, including when patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil, serious adverse effects have occurred. Concomitant use of verapamil with agents that decrease adrenergic function may result in an exaggerated hypotensive response. Animal studies suggest concomitant use of intravenous verapamil and intravenous dantrolene sodium may result in cardiovascular collapse. The clinical relevance of these findings is unknown. Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cimetidine has no effect on intravenous CALAN kinetics. As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein- bound drugs. Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. HMG‐CoA reductase inhibitors: The use of HMG‐CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co‐administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5‐fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and delivery: There have been few controlled studies to determine whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a long history of use of intravenous CALAN in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing mothers: Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric use: Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with intravenous administration in more than 250 patients, about half under 12 months of age and about 25% newborn, indicates that results of treatment are similar to those in adults. However, in rare instances, severe hemodynamic side effects have occurred following the intravenous administration of verapamil in neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients. The most commonly used single doses in patients up to 12 months of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to 0.3 mg/kg of body weight. Most of the patients received the lower dose of 0.1 mg/kg once, but in some cases, the dose was repeated once or twice every 10 to 30 minutes. ADVERSE REACTIONS The following reactions were reported with intravenous verapamil use in controlled U.S. clinical trials involving 324 patients: Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in open clinical trials in more than 7,900 patients was similar. Central nervous system effects: Dizziness (1.2%); headache (1.2%). Although rare, cases of seizures during verapamil injection has been reported. Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). In rare cases of hypersensitivity, broncho/laryngeal spasm accompanied by itch and urticaria has been reported. The following reactions were reported in a few patients: emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, or diaphoresis. Suggested Treatment of Acute Cardiovascular Adverse Reactions* The frequency of these adverse reactions was quite low, and experience with their treatment has been limited. Adverse Proven Effective Supportive Reaction Treatment Treatment Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. Symptomatic Dopamine HCl IV Intravenous hypotenstion Calcium chloride IV fluids requiring Norepinephrine bitartrate IV Trendelenburg treatment Metaraminol bitartrate IV position Isoproterenol HCl IV 2. Bradycardia, AV Isoproterenol HCl IV Intravenous block, Asystole Calcium chloride IV fluids Norepinephrine bitartrate IV (slow drip) Atropine sulfate IV Cardiac pacing 3. Rapid ventricular DC-cardioversion Intravenous rate (due to (high energy may fluids antegrade con- be required) (slow drip) duction in Procainamide IV flutter/fibrilla- Lidocaine HCl IV tion with WPW or LGL syndromes) *Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions (calcium chloride) have been effectively used in treatment of deliberate overdosage with oral verapamil. Clinically significant hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). DOSAGE AND ADMINISTRATION For intravenous use only. CALAN SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ECG AND BLOOD PRESSURE MONITORING. The recommended intravenous doses of CALAN are as follows: Adult: Initial dose—5-10 mg (0.075-0.15 mg/kg body weight) given as an intravenous bolus. Repeat dose—10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. Older patients—The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. Pediatric: Initial dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) should be administered as an intravenous bolus. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) should be Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administered as an intravenous bolus. Do not exceed 5 mg. Repeat dose 0-1 year: 0.1-0.2 mg/kg body weight (usual single dose range: 0.75-2 mg) 30 minutes after the first dose if the initial response is not adequate. 1-15 years: 0.1-0.3 mg/kg body weight (usual single dose range: 2-5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a single dose. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. For stability reasons this product is not recommended for dilution with Sodium Lactate Injection USP in polyvinyl chloride bags. Admixing intravenous CALAN with albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided. CALAN will precipitate in any solution with a pH above 6.0. HOW SUPPLIED All forms are individually packaged. Size NDC Number Carton Size 5-mg (2 ml) ampule 5-mg (2 ml) vial 10-mg (4 ml) vial 5-mg (2 ml) syringe 10-mg (4 ml) syringe 0025-1853-10 0025-1864-05 0025-1874-05 0025-1958-05 0025-1968-05 10 5 5 5 5 Store at 59° to 86°F (15° to 30°C) and protect from light during storage. company logo LAB-0421-2.0 Revised October 2011 Reference ID: 3038095 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.553005	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019038s004lbl.pdf', 'application_number': 19038, 'submission_type': 'SUPPL ', 'submission_number': 4}
11,421	NDA 19-034/S-018-Label Page 1 DILAUDID® and DILAUDID-HP® INJECTION 1 mg/mL, 2 mg/mL, 4mg/mL, and 10 mg/mL (hydromorphone hydrochloride) C-II WARNING: DILAUDID-HP (high potency, 10 mg/mL ampules and vials) is a more concentrated solution of hydromorphone than DILAUDID INJECTION, and is intended for use only in opioid-tolerant patients. Do not confuse DILAUDID-HP with standard parenteral formulations of DILAUDID or other opioids, as overdose and death could result. DILAUDID® INJECTION (1, 2, and 4 mg/mL ampules, sterile solution for parenteral administration) and DILAUDID-HP® contain hydromorphone, a potent Schedule II opioid agonist. Schedule II opioid agonists, including morphine, oxymorphone, hydromorphone, oxycodone, fentanyl and methadone, have the highest potential for abuse and risk of producing respiratory depression. Ethanol, other opioids, and other central nervous system depressants (e.g., sedative-hypnotics, skeletal muscle relaxants) can potentiate the respiratory- depressant effects of hydromorphone and increase the risk of adverse outcome, including death. DESCRIPTION DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid analgesic. The chemical name of DILAUDID (hydromorphone hydrochloride) is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The structural formula is: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 2 M.W. 321.8 DILAUDID INJECTION is available in ampules for parenteral administration. Each 1 mL of sterile solution contains 1 mg, 2 mg, or 4 mg hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid solution. DILAUDID INJECTION ampules are sterile. HIGH POTENCY DILAUDID (DILAUDID-HP) is available in AMBER ampules or single dose vials for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each 1 mL of sterile solution contains 10 mg hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid solution. It is also available as lyophilized DILAUDID-HP for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each single dose vial contains 250 mg sterile, lyophilized hydromorphone HCl to be reconstituted with 25 mL of Sterile Water for Injection USP to provide a solution containing 10 mg/mL. CLINICAL PHARMACOLOGY Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness. Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 3 vomiting and electroencephalographic changes. Many of the effects described below are common to the class of mu-opioid analgesics, which includes morphine, oxycodone, hydrocodone, codeine, and fentanyl. In some instances, data may not exist to demonstrate that DILAUDID INJECTION and DILAUDID-HP possess similar or different effects than those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that DILAUDID INJECTION and DILAUDID-HP would possess these effects. Central Nervous System The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects by combining with these receptors. Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla. Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension. Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of DILAUDID INJECTION or DILAUDID-HP overdose. Gastrointestinal Tract and Other Smooth Muscle Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 4 Cardiovascular System Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes. Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive. Pharmacokinetics and Metabolism Distribution At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 (32%) liters. Metabolism Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Elimination Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6- hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours. Special Populations Hepatic Impairment After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR Tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4 fold in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 5 patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at a lower dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected. As such, the starting dose should be even more conservative (see DOSAGE AND ADMINISTRATION). Renal Impairment After oral administration of hydromorphone at a single 4 mg dose (2 mg Dilaudid IR Tablets), mean exposure to hydromorphone (Cmax and AUC0-48) is increased in patients with impaired renal function by 2-fold, in moderate (CLcr = 40 - 60 mL/min) renal impairment and 3-fold in severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients with severe renal impairment should be even lower. Patients with renal impairment should be closely monitored during dose titration (see DOSAGE AND ADMINISTRATION). Pediatrics Pharmacokinetics of hydromorphone have not been evaluated in children. Geriatric The effect of age on the pharmacokinetics of hydromorphone has not been adequately evaluated. Gender Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have a higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may not be clinically relevant. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 6 Pregnancy and Nursing Mothers Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, and may cause respiratory compromise in newborns when administered during labor or delivery. CLINICAL TRIALS Analgesic effects of single doses of DILAUDID ORAL LIQUID administered to patients with post-surgical pain have been studied in double-blind controlled trials. In one study, both 5 mg and 10 mg of DILAUDID ORAL LIQUID provided significantly more analgesia than placebo. INDICATIONS AND USAGE DILAUDID INJECTION is indicated for the management of pain in patients where an opioid analgesic is appropriate. DILAUDID-HP is indicated for the relief of moderate-to-severe pain in opioid-tolerant patients who require larger than usual doses of opioids to provide adequate pain relief. Because DILAUDID-HP contains 10 mg of hydromorphone hydrochloride per mL, a smaller injection volume can be used than with other parenteral opioid formulations. Discomfort associated with the intramuscular or subcutaneous injection of an unusually large volume of solution can therefore be avoided. CONTRAINDICATIONS DILAUDID INJECTION and DILAUDID-HP are contraindicated in patients with known hypersensitivity to hydromorphone. DILAUDID INJECTION and DILAUDID-HP are contraindicated in patients with respiratory depression in the absence of resuscitative equipment and in patients with status asthmaticus. DILAUDID INJECTION and DILAUDID-HP are also contraindicated for use in obstetrical analgesia. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 7 DILAUDID-HP is contraindicated in patients who are not already receiving large amounts of opioids. WARNINGS DILAUDID-HP (high potency, 10 mg/mL ampules and vials) is a more concentrated solution of hydromorphone than DILAUDID INJECTION, and is intended for use only in opioid-tolerant patients. Do not confuse DILAUDID-HP with standard parenteral formulations of DILAUDID or other opioids, as overdose and death could result. Respiratory Depression Respiratory depression is the chief hazard of DILAUDID INJECTION and DILAUDID-HP. Respiratory depression occurs most frequently in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may dangerously decrease pulmonary ventilation. DILAUDID INJECTION and DILAUDID-HP should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative non-opioid analgesics should be considered, and DILAUDID should be employed only under careful medical supervision at the lowest effective dose in such patients. Misuse, Abuse, and Diversion of Opioids DILAUDID INJECTION and DILAUDID-HP contain hydromorphone, and opioid agonist of the morphine-type, which is a potent Schedule II, controlled substance. Schedule II opioid agonists, including morphine, oxycodone, oxymorphone, fentanyl and methadone, have the highest potential for abuse and risk of fatal respiratory depression. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 8 DILAUDID INJECTION and DILAUDID-HP can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing DILAUDID INJECTION or DILAUDID-HP in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients, however, they will require intensive monitoring for signs of abuse. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Alcohol, other opioids and central nervous system depressants (sedative-hypnotics) potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death. Neonatal Withdrawal Syndrome Infants born to mothers physically dependent on DILAUDID INJECTION or DILAUDID-HP will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see DRUG ABUSE AND DEPENDENCE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of DILAUDID INJECTION and DILAUDID-HP with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including DILAUDID INJECTION and DILAUDID-HP may produce effects on pupillary response and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 9 consciousness which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries. Hypotensive Effect Opioid analgesics, including DILAUDID INJECTION and DILAUDID-HP, may cause severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics (see PRECAUTIONS - Drug Interactions). DILAUDID INJECTION and DILAUDID-HP may produce orthostatic hypotension in ambulatory patients. DILAUDID INJECTION and DILAUDID-HP should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Sulfites DILAUDID INJECTION and DILAUDID-HP contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS General Because of its high concentration, the delivery of precise doses of DILAUDID-HP may be difficult if low doses of hydromorphone are required. Therefore, DILAUDID-HP should be used only if the amount of hydromorphone required can be delivered accurately with this formulation. Gastrointestinal Effects DILAUDID INJECTION and DILAUDID-HP should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus, because hydromorphone diminishes This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 10 the propulsive peristaltic wave in the gastrointestinal tract and may prolong the obstruction. The administration of DILAUDID INJECTION or DILAUDID-HP may obscure the diagnosis or clinical course in patients with acute abdominal condition. Use in Pancreatic/Biliary Tract Disease DILAUDID INJECTION and DILAUDID-HP should be used with caution in patients with biliary tract disease, including acute pancreatitis, as hydromorphone may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions. Special Risk Patients DILAUDID INJECTION and DILAUDID-HP should be given with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis. In the case of DILAUDID-HP, however, the patient is presumed to be receiving an opioid to which he or she exhibits tolerance and the initial dose of DILAUDID-HP selected should be estimated based on the relative potency of hydromorphone and the opioid previously used by the patient. (see DOSAGE AND ADMINISTRATION). The administration of opioid analgesics including DILAUDID INJECTION and DILAUDID- HP may aggravate preexisting convulsions in patients with convulsive disorders. Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration at very high doses is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus. Use in Drug and Alcohol Dependent Patients DILAUDID INJECTION and DILAUDID-HP should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 11 tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID INJECTION or DILAUDID-HP in combination with other CNS depressant drugs can result in serious risk to the patient. Hydromorphone is an opioid with no approved use in the management of addictive disorders. Driving and Operating Machinery DILAUDID INJECTION and DILAUDID-HP may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery). Patients should be cautioned accordingly. DILAUDID INJECTION and DILAUDID-HP may produce orthostatic hypotension in ambulatory patients. Tolerance and Physical Dependence Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids used regularly should not be abruptly discontinued. Information for Patients/Caregivers Patients receiving DILAUDID (hydromorphone hydrochloride) or their caregivers should be given the following information by the physician, nurse, or pharmacist: 1. Patients should be aware that DILAUDID INJECTION and DILAUDID-HP contain hydromorphone, which is a morphine-like substance and which could cause severe adverse effects including respiratory depression and even death if not taken according to the prescriber’s directions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 12 2. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 3. Patients should be advised not to adjust the dose of DILAUDID INJECTION or DILAUDID-HP without consulting the prescribing professional. 4. Patients should be advised that DILAUDID INJECTION and DILAUDID-HP may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). 5. Patients should not combine DILAUDID INJECTION or DILAUDID-HP with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death. 6. Women of childbearing potential who become, or are planning to become pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. 7. Patients should be advised that DILAUDID INJECTION and DILAUDID-HP are potential drugs of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. 8. Patients should be advised that if they have been receiving treatment with DILAUDID INJECTION or DILAUDID-HP for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the DILAUDID INJECTION or DILAUDID-HP dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication. 9. Patients should be instructed to keep DILAUDID INJECTION and DILAUDID-HP in a secure place out of the reach of children. Drug Interactions Drug Interactions with other CNS Depressants The concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 13 or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Opioid analgesics, including DILAUDID INJECTION and DILAUDID-HP, may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression. Interactions with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients. Parenteral Administration DILAUDID INJECTION may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression. Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration at very high doses is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus. Experience with administration of DILAUDID-HP by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted in animals. Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay, or the human lymphocytes chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse micronucleus assay. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 14 No effects on fertility, reproductive performance, or reproductive organ morphology were observed in male or female rats given oral doses up to 7 mg/kg/day which is equivalent to and 3-fold higher than the human dose of DILAUDID-HP when substituted for ORAL LIQUID or 8 mg TABLET, respectively, on a body surface area basis. PREGNANCY PREGNANCY CATEGORY C No effects on teratogenicity or embryotoxicity were observed in female rats given oral doses up to 7 mg/kg/day which is equivalent to and 3-fold higher than the human dose of DILAUDID-HP, on a body surface area basis. Hydromorphone produced skull malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg during the peak of organogenesis (gestation days 8-9). The skull malformations were observed at doses approximately 2-fold and 7-fold higher than the human dose of DILAUDID-HP when substituted for ORAL LIQUID or 8 mg TABLET, respectively, on a body surface area basis. There are no adequate and well-controlled studies of DILAUDID INJECTION or DILAUDID-HP in pregnant women. Hydromorphone crosses the placenta, resulting in fetal exposures. DILAUDID INJECTION or DILAUDID-HP should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND DEPENDENCE). Nonteratogenic Effects Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 15 Labor and Delivery DILAUDID INJECTION and DILAUDID-HP are contraindicated in Labor and Delivery (see CONTRAINDICATIONS). Nursing Mothers Low levels of opioid analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving DILAUDID INJECTION or DILAUDID-HP since it, and other drugs in this class, may be excreted in the milk. Pediatric Use Safety and effectiveness have not been established. Geriatric Use Clinical studies of DILAUDID INJECTION and DILAUDID-HP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see DOSAGE AND ADMINISTRATION - Individualization Of Dosage and PRECAUTIONS ). ADVERSE REACTIONS The major hazards of DILAUDID INJECTION and DILAUDID-HP include respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred. The most frequently observed adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 16 Less Frequently Observed Adverse Reactions General and CNS Weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity, paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and disorientation, visual disturbances, insomnia, increased intracranial pressure Cardiovascular Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension Respiratory Bronchospasm and laryngospasm Gastrointestinal Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps, taste alterations Genitourinary Urinary retention or hesitancy, antidiuretic effects Dermatologic Urticaria, other skin rashes, wheal and flare over the vein with intravenous injection, diaphoresis Other In clinical trials, neither local tissue irritation nor induration was observed at the site of subcutaneous injection of DILAUDID-HP; pain at the injection site was rarely observed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 17 OVERDOSAGE Acute overdosage with DILAUDID INJECTION or DILAUDID-HP is characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac arrest and death may occur. Hydromorphone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. In the treatment of overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to DILAUDID INJECTION or DILAUDID-HP. Therefore, an appropriate dose of this antagonist should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected to be physically dependent on DILAUDID INJECTION or DILAUDID-HP. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Since the duration of action of DILAUDID INJECTION and DILAUDID-HP may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. Apply other supportive measures when indicated. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. Such agents This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 18 should be administered cautiously to persons who are known, or suspected to be physically dependent on hydromorphone. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. In an individual physically dependant on opioids, administration of the usual dose antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and titrated with smaller than usual doses. DOSAGE AND ADMINISTRATION DILAUDID INJECTION The usual starting dose is 1-2 mg subcutaneously or intramuscularly every 4 to 6 hours as necessary for pain control. The dose should be adjusted according to the severity of pain, as well as the patient's underlying disease, age, and size. Patients with terminal cancer may be tolerant to opioid analgesics and may, therefore, require higher doses for adequate pain relief. Intravenous or subcutaneous administration is usually not painful. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes, depending on the dose. A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect. Patients with hepatic and renal impairment should be started on a lower starting dose (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism). If DILAUDID INJECTION is substituted for a different opioid analgesic, the equivalency tables below should be used as a guide to determine the appropriate dose of DILAUDID INJECTION. DILAUDID-HP DILAUDID-HP SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. DILAUDID-HP is indicated for relief of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 19 moderate-to-severe pain in opioid-tolerant patients. Thus, these patients will already have been treated with other opioid analgesics. If the patient is being changed from regular DILAUDID to DILAUDID-HP, similar doses should be used, depending on the patient's clinical response to the drug. If DILAUDID-HP is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of DILAUDID-HP. Patients with hepatic and renal impairment should be started on a lower starting dose (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism). OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC POTENCY* DRUG SUBSTANCE IM OR SC** DOSE ORAL DOSE Morphine Sulfate 10 mg 40 - 60 mg Hydromorphone HCl 1.3 – 2 mg 6.5 – 7.5 mg Oxymorphone HCl 1 – 1.1 mg 6.6 mg Levorphanol tartrate 2 – 2.3 mg 4 mg Meperidine HCl (pethidine HCl) 75 – 100 mg 300 – 400 mg Methadone HCl 10 mg 10 – 20 mg Nalbuphine HCl 12 mg ___ Butorphanol tartrate 1.5 – 2.5 mg ___ * Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references comparing opioid analgesics in cancer and severe pain. ** IM = intramuscular; SC = subcutaneous Experience with administration of DILAUDID-HP by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes. A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in DILAUDID INJECTION and DILAUDID-HP ampules. No loss of potency has been demonstrated. DILAUDID INJECTION and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 20 DILAUDID-HP injection are physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions. 500 mg/50 mL Vial* To use this single dose presentation, do not penetrate the stopper with a syringe. Instead, remove both the aluminum flipseal and rubber stopper in a suitable work area such as under a laminar flow hood (or equivalent clean air compounding area). The contents may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner. Reconstitution of Sterile Lyophilized DILAUDID-HP 250 mg* Reconstitute immediately prior to use with 25 mL of Sterile Water for Injection USP to provide a sterile solution containing 10 mg/mL. The Packaging Of These Products Contain Dry Natural Rubber. Individualization Of Dosage The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized for any given patient, since adverse events can occur at doses that may not provide complete freedom from pain. Safe and effective administration of opioid analgesics to patients with acute or chronic pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, etiology, and pathophysiology), as well as the concurrent medical status of the patient, will affect selection of the starting dosage. In patients receiving opioids, both the dose and duration of analgesia will vary substantially depending on the patient's opioid tolerance. The dose should be selected and adjusted so that at least 3-4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of DILAUDID INJECTION or DILAUDID-HP should be based on prior opioid usage. This should be done by converting the total daily usage of the previous opioid to an equivalent total daily dosage of DILAUDID INJECTION or DILAUDID-HP using an equianalgesic table (see above). For opioids not in the table, first estimate the equivalent total daily usage of oral morphine, then use the table to find the equivalent total daily dosage of DILAUDID INJECTION or DILAUDID-HP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 21 Once the total daily dosage of DILAUDID INJECTION or DILAUDID-HP has been estimated, it should be divided into the desired number of doses. Since there is individual variation in response to different opioid drugs, only 1/2 to 2/3 of the estimated dose of DILAUDID INJECTION or DILAUDID-HP calculated from equivalence tables should be given for the first few doses, then increased as needed according to the patient's response. Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment with a consequent increase in exposure, patients with hepatic and renal impairment should be started on a lower starting dose (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism). In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5-15% of the total daily usage may be administered every two hours on an "as-needed" basis. Periodic reassessment after the initial dosing is always required. If pain management is not satisfactory, and in the absence of significant opioid-induced adverse events, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, the hydromorphone hydrochloride dose should be reduced. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia than the absolute dose of opioid employed. DRUG ABUSE AND DEPENDENCE DILAUDID INJECTION and DILAUDID-HP contain hydromorphone, a Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine, oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion. Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage, but it may occur after as little as a week of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 22 opioid use. Physical dependence and tolerance are separate and distinct from abuse and addiction. Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with, forging or counterfeiting prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non- medical purposes, often in combination with other psychoactive substances. Since DILAUDID INJECTION and DILAUDID-HP may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. DILAUDID INJECTION and DILAUDID-HP are intended for parenteral use only under the direct supervision of an appropriately licensed health care provider. Misuse or abuse of DILAUDID INJECTION or DILAUDID-HP poses a risk of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 23 SAFETY AND HANDLING INSTRUCTIONS DILAUDID INJECTION and DILAUDID-HP pose little risk of direct exposure to health care personnel and should be handled and disposed of prudently in accordance with hospital or institutional policy. Patients and their families should be instructed to flush any DILAUDID INJECTION or DILAUDID-HP that is no longer needed. Access to abusable drugs such as DILAUDID INJECTION and DILAUDID-HP presents an occupational hazard for addiction in the health care industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect health care workers. Implementation of more effective accounting procedures and measures to restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-administration by health care providers. HOW SUPPLIED # Name Strength Dosage Form Appearance Package Type Package Qty NDC 1 DILAUDID-HP INJECTION 10 MILLIGRAM SOLUTION (C42986) AMPULE (C43165) 1 MILLILITER 2 DILAUDID-HP INJECTION 50 MILLIGRAM SOLUTION (C42986) AMPULE (C43165) 5 MILLILITER 3 DILAUDID-HP INJECTION 500 MILLIGRAM SOLUTION (C42986) VIAL, SINGLE- DOSE (C43215) 50 MILLILITER 0074- 2453- 51 4 DILAUDID-HP INJECTION 250 MILLIGRAM POWDER (C42972) VIAL, SINGLE- DOSE (C43215) 25 MILLILITER 0074- 2455- 31 DILAUDID INJECTION DILAUDID INJECTION (hydromorphone hydrochloride) is available in CLEAR ampules. Each 1 mL of sterile solution contains 1 mg, 2 mg, or 4 mg hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid solution. DILAUDID INJECTION ampules are sterile and are supplied as follows: NDC 59011-441-10: Box of ten 1 mg/mL ampules NDC 59011-442-10: Box of ten 2 mg/mL ampules NDC 59011-442-25: Box of 25 2 mg/mL ampules NDC 59011-444-10: Box of ten 4 mg/mL ampules This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-034/S-018-Label Page 24 DILAUDID-HP DILAUDID-HP (hydromorphone hydrochloride) is available in AMBER ampules and single dose vials. Each 1mL of sterile solution contains 10 mg hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid solution. No added preservative. DILAUDID-HP Sterile Lyophilized Powder contains 250 mg of sterile, lyophilized hydromorphone HCl in a Single Dose Vial. DILAUDID-HP is supplied as follows: NDC 59011-445-01: Box of ten 1mL (10 mg) ampules NDC 59011-445-05: Box of ten 5mL (50 mg) ampules NDC 59011-445-50: One 50 mL (500 mg) Single-Dose Vial NDC 59011-445-25: One 250 mg single dose vial* *The Packaging of These Products Contain Dry Natural Rubber Storage PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. A Schedule C-II Narcotic. DEA Order Form Required. Revised June 2008 Manufactured by Hospira, Inc., Lake Forest, IL 60045, U.S.A. for Purdue Pharma L.P. Stamford, CT 06901-3431 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 59011-445-50 NDC 59011-445-50 only One 50 mL (500 mg) Single-Dose Vial NDC 59011-445-50 One 50 mL (500 mg) Single-Dose Vial ® SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS 10 mg/mL 500 mg per vial 10 mg/mL 500 mg per vial SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS STORAGE: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. CA-1864 301802-0B Usual dose: See package insert for full prescribing information. This vial contains 500 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. One 50 mL (500 mg) Single-Dose Vial SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS. ® 10 mg/mL 500 mg per vial Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 500 mg Ampule-50 mL File Resource # NA Component # 301802-0P Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 245 black Special Instructions: Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 ® 10 mg/mL 500 mg per vial ® 301802-0P hp:301802-0A 6/5/08 9:07 AM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ® NDC 59011-445-05 Ten 5 mL (50 mg) Ampules SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS. SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS. Storage: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59°- 86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Usual dose: See package insert for full prescribing information. Each ampule contains 50 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. Each ampule contains a sufficient amount to permit withdrawal of 5 mL. This unit package is not to be broken for resale. See bottom of carton for lot number and expiration date. 10mg per mL 50 mg per ampule ® 10 mg/mL 50 mg per ampule Ten 5 mL (50 mg) Ampules CA-1747 301800-0A Ten 5 mL (50 mg) Ampules ® NDC 59011-445-05 Ten 5 mL (50 mg) Ampules SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS. only 10mg per mL 50 mg per ampule ® 10 mg/mL 50 mg per ampule ® 10 mg/mL 50 mg per ampule only PMS 162 black Special Instructions: Document Colors Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 50 mg Ampule-5 mL File Resource # NA Component # 301800-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 301800-0P hp car:CA-0837 6/6/08 12:35 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ® NDC 59011-445-01 10mg per mL Storage: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59°- 86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Usual dose: See package insert for full prescribing information. Each ampule contains 10 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. Each ampule contains a sufficient amount to permit withdrawal of 1mL. This unit package is not to be broken for resale. See side panel for lot number and expiration date. NDC 59011-445-01 Ten 1 mL (10 mg) Ampules 10 mg per mL ® only SPECIAL HIGH-POTENCY FORMULATION SPECIAL HIGH-POTENCY FORMULATION SPECIAL HIGH-POTENCY FORMULATION 10mg per mL CA-1745 301799-0A 10 mg/mL 10 mg/mL 10 mg/mL Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 10 mg 10 Ampules-1 mL File Resource # NA Component # 301799-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 245 black Special Instructions: Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 ® Ten 1 mL (10 mg) Ampules ® ® 301799-0P hp 1 ml3:301799-0A 6/5/08 9:17 AM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 59011-444-10 Ten 1 mL Ampules 4 mg per mL Storage: Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Each ampule contains 4 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added pre- servative. Each ampule contains a sufficient amount to permit withdrawal of 1mL. This unit package is not to be broken for resale. See side panel for lot number and expiration date. Usual dose by injection: See package insert for full prescribing information. NDC 59011-444-10 Ten 1 mL Ampules Ten 1 mL Ampules 4 mg per mL 4 mg per mL CA-1744 301798-0A 4 mg/mL 4 mg/mL Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 4 mg 10 Ampules-1 mL File Resource # NA Component # 301798-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 116 black Special Instructions: Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 only 301798-P 4mg amp car:301798-0A 6/6/08 12:16 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 59011-442-10 Ten 1 mL Ampules 2 mg per mL Storage: Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Each ampule contains 2 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. Each ampule contains a sufficient amount to permit withdrawal of 1 mL. This unit package is not to be broken for resale. See side panel for lot number and expiration date. Usual dose by injection: See package insert for full prescribing information. NDC 59011-442-10 Ten 1 mL Ampules 2 mg per mL Ten 1 mL Ampules 2 mg per mL CA-1742 301797-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 10 Ampules-1 mL File Resource # NA Component # 301797-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 198 black Special Instructions: Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 2 mg/mL 2 mg/mL only 301797-0P:301797-0A 6/6/08 12:28 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 59011-442-25 25 1 mL Ampules Storage: Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Each ampule contains 2 mg hydromorphone hydrochloride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. Each ampule contains a sufficient amount to permit withdrawal of 1 mL. This unit package is not to be broken for resale. See side panel for lot number and expiration date. Usual dose by injection: See package insert for full prescribing information. 2 mg per mL 2 mg per mL NDC 59011-442-25 25 1 mL Ampules 2 mg per mL 2 mg per mL 2 mg per mL 25 1 mL Ampules CA-1743 301796-0A Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 only 301796-0P.qxp:CA-1688 6/6/08 12:32 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 2 mg 25 Ampules-1 mL File Resource # NA Component # 301796-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 198 black Special Instructions: 301796-0P.qxp:CA-1688 6/6/08 12:32 PM Page 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DIRECTIONS FOR RECONSTITUTION: Reconstitute lyophilized hydromorphone by aseptically adding 25 mL of Sterile Water for Injection, USP, to provide a solution containing 10 mg/mL. Shake vial to ensure complete mixing. Use immediately after reconstitution. Discard any unused portion. USUAL DOSE: See package insert. Storage: Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [See USP Controlled Room Temperature]. Protect from light. Single Dose Vial FOR USE IN THE PREPARATION OF LARGE VOLUME PARENTERALS Sterile Lyophilized Powder 250 mg RL-2430 301791-0A Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 only Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 250 mg File Resource # NA Component # 301791-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors Reflex Blue C black Special Instructions: (01)10359011446251 301791-0P2:301791-0A 6/6/08 12:39 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPECIAL HIGH-POTENCY FORMULA. FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS. Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 RL-2574 301790-0B 10 mg/mL 500 mg per vial Usual dose: See package insert for full prescribing information. Storage: Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. only Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 500 mg Ampule-50 mL File Resource # NA Component # 301790-0B Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 294 black (01)10359011445506 ® One 50 mL (500 mg) Single-Dose Vial 301790-0P hp lab:301790-0A 6/4/08 1:42 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RL-2429 301789-0A Injection 10 mg/mL only Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 FOR USE IN THE PREPARATION OF LARGE-VOLUME PARENTERAL SOLUTIONS Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 50 mg Ampule-5 mL File Resource # NA Component # 301789-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 245 black white (01)10359011445056 5mL(50 mg)Ampule 301789-0P:301789-0A 6/4/08 3:50 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 10 mg 10x1 mL Ampules File Resource # NA Component # 301788-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 245 black white Special Instructions: RL-2427 301788-0A (01)10359011445018 Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 Injection 10 mg/mL 1mL(10 mg) Ampule only 301788-0P:301788-0A 6/4/08 4:23 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RL-2426 301787-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 4 mg Ampule-1 mL File Resource # NA Component # 301787-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 116 black white Special Instructions: (01)10359011444103 Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 only 4 mg/mL 301787-0P:301787-0A 6/6/08 11:57 AM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RL-2425 301786-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 2 mg Ampule-1 mL File Resource # NA Component # 301786-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 198 black White (01)10359011442253 Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 only 2 mg/mL 301786-0P:301786-0A 6/4/08 4:21 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RL-2424 301785-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 2 mg Ampule-1 mL File Resource # NA Component # 301785-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 198 black White Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 only (01)10359011442109 2 mg/mL 301785-0P:301785-0A 6/4/08 4:16 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RL-2423 301784-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 1 mg/ml 1ml File Recource # NA Component # 301784-0A Component Type Label Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 284 black white Special Instructions: Mfd for: Purdue Pharma L.P. Stamford, CT 06901-3431 (01)10359011441102 only 1 mg/mL 301784-0P.qxd:301784-0A.qxd 6/4/08 3:57 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDC 59011-441-10 Ten 1 mL Ampules 1mg per mL Storage: Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. USE THIS CARTON TO PROTECT CONTENTS FROM LIGHT. Each ampule contains 1 mg hydromorphone hydrochlo- ride in 0.2% sodium citrate, 0.2% citric acid solution. No added preservative. Each ampule contains a sufficient amount to permit withdrawal of 1mL. This unit package is not to be broken for resale. See side panel for lot number and expiration date. Usual dose by injection: See package insert for full prescribing information. NDC 59011-441-10 Ten 1 mL Ampules 1mg per mL only Ten 1 mL Ampules 1mg per mL CA-1741 301803-0A Purdue 1 Stamford Forum, Stamford, CT 06901-3431 Project Name Dilaudid 10 Ampules-1 mL File Resource # NA Component # 301803-0A Component Type Carton Dimensions See die line Software Quark Xpress 7.0 Document Colors PMS 284 black Special Instructions: Manufactured for: Purdue Pharma L.P. Stamford, CT 06901-3431 By: Hospira, Inc. Lake Forest, IL 60045 1 mg/mL 1 mg/mL 301803-0P:301803-0A 6/6/08 1:22 PM Page 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.578711	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019034s018lbl.pdf', 'application_number': 19034, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,424	1 INDIUM In 111 OXYQUINOLINE SOLUTION For the Radiolabeling of Autologous Leukocytes Rx ONLY Diagnostic—For intravenous use For single dose, single use only DESCRIPTION Indium In 111 oxyquinoline (oxine) is a diagnostic radiopharmaceutical intended for radiolabeling autologous leukocytes. It is supplied as a sterile, non-pyrogenic, isotonic aqueous solution with a pH range of 6.5 to 7.5. Each mL of the solution contains 37 MBq, 1 mCi of indium In 111 [no carrier added, >1.85 GBq/µg indium (>50 mCi/µg indium)] at calibration time, 50 µg oxyquinoline, 100 µg polysorbate 80, and 6 mg of HEPES (N-2-hydroxyethyl- piperazine-N'-2-ethane sulfonic acid) buffer in 0.75% sodium chloride solution. The drug is intended for single use only and contains no bacteriostatic agent. The radionuclidic impurity limit for indium 114m is not greater than 37 kBq, 1 µCi of indium 114m per 37 MBq, 1 mCi of indium In 111 at the time of calibration. The radionuclidic composition at expiration time is not less than 99.75% of indium In 111 and not more than 0.25% of indium In 114m/114. Chemical name: Indium In 111 Oxyquinoline. The precise structure of the indium In 111 oxyquinoline complex is unknown at this time. The empirical formula is (C9H6NO)3 In 111. PHYSICAL CHARACTERISTICS Indium In 111 decays by electron capture with a physical half-life of 67.2 hours (2.8 days). The energies of the photons that are useful for detection and imaging studies are listed in Table 1. Table 1. Principal Radiation Emission Data1 Radiation Mean %/ Disintegration Mean Energy (keV) Gamma 2 90.2 171.3 Gamma 3 94 245.4 1 Kocher, David C., "Radioactive Decay Data Tables", DOE/TIC-11026, 115 (1981). EXTERNAL RADIATION The exposure rate constant for 37 MBq, 1 mCi indium In 111 is 8.3 × 10-4 C/kg/h (3.21 R/h) at 1 cm. The first half value thickness of lead (Pb) for indium In 111 is 0.023 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 0.834 cm of lead will decrease the external radiation exposure by a factor of about 1,000. 2 Table 2. Radiation Attenuation by Lead Shielding2 Shield Thickness (Pb) cm Coefficient of Attenuation 0.023 0.5 0.203 10-1 0.513 10-2 0.834 10-3 1.12 10-4 2 Data supplied by Oak Ridge Associated Universities, Radiopharmaceutical Internal Dose Information Center, 1984. These estimates of attenuation do not take into consideration the presence of longer-lived contaminants with higher energy photons, namely indium In 114m/114. To allow correction for physical decay of indium In 111, the fractions that remain at selected intervals before and after the time of calibration are shown in Table 3. Table 3. Physical Decay Chart for Indium In 111, Half-life 67.2 hours Day Fraction Remaining Day Fraction Remaining -2 1.641 2 0.610 -1 1.281 3 0.476 0* 1.000 4 0.372 1 0.781 5 0.290 * Calibration Time CLINICAL PHARMACOLOGY Indium forms a saturated (1:3) complex with oxyquinoline. The complex is neutral and lipid- soluble, which enables it to penetrate the cell membrane. Within the cell, indium becomes firmly attached to cytoplasmic components; the liberated oxyquinoline is released by the cell. It is thought likely that the mechanism of labeling cells with indium In 111 oxyquinoline involves an exchange reaction between the oxyquinoline carrier and subcellular components which chelate indium more strongly than oxyquinoline. The low stability constant of the oxyquinoline complex, estimated at approximately 10, supports this theory. Following the recommended leukocyte cell labeling procedure, approximately 77% of the added indium In 111 oxyquinoline is incorporated in the resulting cell pellet (which represents approximately 3-4 × 108 WBC). 3 Cell clumping can occur and was found in about one fifth of the leukocyte preparations examined. The presence of red blood cells or plasma will lead to reduced leukocyte labeling efficiency. Transferrin in plasma competes for indium In 111 oxyquinoline. After injection of labeled leukocytes into normal volunteers, about 30% of the dose is taken up by spleen and 30% by liver, reaching a plateau at 2-48 hours after injection. No significant clearance of radioactivity is observed at 72 hours in these two organs. Pulmonary uptake is 4- 7.5% at 10 minutes but is lost rapidly; pulmonary radioactivity is usually visible in scans only up to about 4 hours after injection. The human biodistribution studies in three normal subjects injected with indium In 111 oxyquinoline labeled leukocytes indicate a biexponential disappearance of indium In 111 from the blood when monitored for up to 72 hours. Between 9.5 to 24.4% of the injected dose remains in whole blood and clears with a biological half-time of 2.8 to 5.5 hours. The remainder (13- 18%) clears from blood with a biological half-time of 64 to 116 hours. Elimination from the body of injected indium In 111 oxyquinoline is probably mainly through decay to stable cadmium since only a negligible amount (less than 1%) of the dose is excreted in feces and urine in 24 hours. Clearance from whole blood and biological distribution can vary considerably with the individual recipient, the condition of the injected cells and labeling techniques used. Release of radioactivity from the labeled cells is about 3% at 1 hour and 24% at 24 hours. Clearance from liver and spleen, for the purpose of calculating the radiation dose, is assumed to be equal to the physical half-life of indium In 111 (67.2 hours). INDICATIONS AND USAGE Indium In 111 oxyquinoline is indicated for radiolabeling autologous leukocytes. Indium In 111 oxyquinoline labeled leukocytes may be used as an adjunct in the detection of inflammatory processes to which leukocytes migrate, such as those associated with abscesses or other infection, following reinjection and detection by appropriate imaging procedures. The degree of accuracy may vary with labeling techniques and with the size, location and nature of the inflammatory process. Indium In 111 oxyquinoline labeled leukocyte imaging is not the preferred technique for the initial evaluation of patients with a high clinical probability of an abscess in a known location. Ultrasound or computed tomography may provide a better anatomical delineation of the infectious process and information may be obtained more quickly than with labeled leukocytes. If localization by these techniques is successful, labeled leukocytes should not be used as a confirmatory procedure. If localization or diagnosis by these methods fails or is ambiguous, indium In 111 oxyquinoline labeled leukocyte imaging may be appropriate. 4 CONTRAINDICATIONS None known. WARNINGS The content of the vial of indium In 111 oxyquinoline solution is intended only for use in the preparation of indium In 111 oxyquinoline labeled autologous leukocytes, and is not to be administered directly. Autologous leukocyte labeling is not recommended in leukopenic patients because of the small number of available leukocytes. Due to radiation exposure, indium In 111 oxyquinoline labeled leukocytes could cause fetal harm when administered to pregnant women. If this radiopharmaceutical is used during pregnancy, the patient should be informed of the potential hazard to the fetus. Indium In 111 oxyquinoline labeled autologous leukocytes should be used only when the benefit to be obtained exceeds the risks involved in children under eighteen years of age owing to the high radiation burden and the potential for delayed manifestation of long-term adverse effects. PRECAUTIONS Clumping of cells may produce focal accumulations of radioactivity in lungs which do not wash out in 24 hours and thus may lead to false positive results. This phenomenon can be detected by imaging the chest immediately after injection. The normally high uptake of indium In 111 oxyquinoline labeled leukocytes by spleen and liver may mask inflammatory lesions in these organs. Labeled leukocytes have been observed to accumulate in the colon and accessory spleens of patients with or without disease. Chemotaxis of granulocytes deteriorates during storage and loss of chemotaxis may cause false negative scans. The spontaneous release of indium In 111 has been reported to range from about 3% at one hour to 24% at 24 hours [ten Berge, R.J.M., Natarajan, A.T., Hardeman, M.R., et al, Labeling with indium In 111 has detrimental effects on human lymphocytes, Journal of Nuclear Medicine, 24, 615-620 (1983)]. The maximum amount of time recommended between drawing the blood and reinjection should not exceed 5 hours. It is recommended that the labeled cells be used within one hour of preparation, if possible and in no case more than three hours after preparation. Plasma and red cell contamination impairs labeling efficiency of leukocytes. Hemolyzed blood in labeled leukocytes may produce heart pool activity and should be avoided. Cell aggregates of various degrees have been reported. Cell labeling techniques and standing of cell preparation may be contributing factors. Nuclear medicine procedures involving withdrawal and reinjection of blood have the potential for transmission of blood borne pathogens. Procedures should be implemented to avoid administration errors and viral contamination of personnel during blood product labeling. A system of checks similar to the ones used for administering blood transfusions should be routine. 5 General Strict aseptic techniques should be used to maintain sterility throughout the procedures for using this product. Do not use after the expiration time and date (5 days after calibration time) stated on the label. The contents of the vial are radioactive. Adequate shielding of the preparation must be maintained at all times. Indium In 111 oxyquinoline, like other radioactive drugs, must be handled with care and appropriate safety measures should be used to minimize radiation exposure to clinical personnel. Care should also be taken to minimize radiation exposure to the patient consistent with proper patient management. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radio- nuclides. Carcinogenesis, Mutagenesis, Impairment of Fertility Although earlier studies suggested that oxyquinoline (oxine) might have carcinogenic potential, recent studies have found no evidence of carcinogenicity in either rats or mice given oxyquinoline in feed at concentrations of 1,500 or 3,000 ppm for 103 weeks. It has been reported [ten Berge, R.J.M., Natarajan, A.T., Hardeman, M.R., et al, Labeling with indium In 111 has detrimental effects on human lymphocytes, Journal of Nuclear Medicine, 24, 615-620 (1983)] that human lymphocytes labeled with recommended concentrations of indium In 111 oxyquinoline showed chromosome aberrations consisting of gaps, breaks and exchanges that appear to be radiation induced. At 555 kBq/107, 15 µCi/107 lymphocytes 93% of the cells were reported to be abnormal. The oncogenic potential of such lymphocytes has not been studied. It has been reported that the radiation dose to 108 leukocytes is 9 × 104 mGy (0.9 × 104 rads) from 18.5 MBq, 500 µCi [Goodwin, David A., Cell labeling with oxine chelates of radioactive metal ions: Techniques and clinical implications, Journal of Nuclear Medicine, 19, 557-559 (1978)]. Studies have not been performed to evaluate whether indium In 111 oxyquinoline affects fertility in male or female laboratory animals or humans. Pregnancy Category C Animal reproduction studies have not been conducted with Indium In 111 Oxyquinoline labeled leukocytes. It is also not known whether Indium In 111 Oxyquinoline labeled leukocytes can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. However, Indium Nitrate, a closely related compound, was teratogenic and embryopathic in hamsters. Indium In 111 Oxyquinoline labeled leukocytes should be given to a pregnant woman only if clearly needed. 6 Ideally, examinations using radiopharmaceuticals, especially those elective in nature, in women of childbearing capability should be performed during the first few (approximately ten) days following the onset of menses. Nursing Mothers It is reported that indium 111 is secreted in human milk following administration of indium In 111 labeled leukocytes. Therefore, formula feedings should be substituted for breast feedings. Pediatric Use Safety and effectiveness in pediatric patients below age 18 have not been established (See Warnings). Geriatric Use Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Sensitivity reactions (urticaria) have been reported. The presence of fever may mask pyrogenic reactions from indium In 111 oxyquinoline labeled leukocytes. The possibility of delayed adverse reactions has not been studied. DOSAGE AND ADMINISTRATION The recommended adult (70 kg) dose of indium In 111 oxyquinoline labeled autologous leukocytes is 7.4 to 18.5 MBq, 200-500 µCi. Indium In 111 oxyquinoline solution is intended for the radiolabeling of autologous leukocytes. The indium In 111 oxyquinoline labeled autologous leukocytes are administered intravenously. Imaging is recommended at approximately 24 hours post injection. Typically, anterior and posterior views of the chest, abdomen and pelvis should be obtained with other views as required. Aseptic procedures and a shielded syringe should be employed in the withdrawal of indium In 111 oxyquinoline from the vial. Similar procedures should be employed during the labeling procedure and the administration of the labeled leukocytes to the patient. The user should wear waterproof gloves during the entire procedure. The patient's dose should be measured by a suitable radioactivity calibration system immediately before administration. At this time, the leukocyte preparation should be checked for gross clumping and red blood cell contamination. RADIATION DOSIMETRY The estimated absorbed radiation doses to an adult patient weighing 70 kg from an intravenous dose of 18.5 MBq, 500 µCi of indium In 111 oxyquinoline labeled leukocytes including contributions from indium In 114m/114 as a radionuclidic impurity are shown in Table 4. 7 Table 4. Radiation Dose Estimate in a 70 kg Human for 18.5 MBq, 500 µCi at Expiry of Indium In 111 (99.75%) Oxyquinoline labeled leukocytes with Indium In 114m/114 (0.25%) Organ mGy/18.5 MBq In 111 Rads/500 µCi In 111 Spleen 130 13 Liver 19 1.9 Red Marrow 13 1.3 Skeleton 3.64 0.364 Testes 0.1 0.01 Ovaries 1.9 0.19 Total Body 3.1 0.31 Organ mGy/46.25 kBq In 114m/114 Rads/1.25 µCi In 114m/114 Spleen 70 7 Liver 7.1 0.71 Red Marrow 6.9 0.69 Skeleton 0.85 0.085 Testes 0.04 0.004 Ovaries 0.06 0.006 Total Body 0.6 0.06 Organ Total Dose in mGy Total Dose in Rads Spleen 200 20 Liver 26.6 2.66 Red Marrow 19.9 1.99 Skeleton 4.5 0.45 Testes 0.14 0.014 Ovaries 2.0 0.2 Total Body 3.7 0.37 Assumptions: 30% to spleen, 30% to liver, 34% to red marrow, 6% to remainder of body, with no excretion. The dose of radiation absorbed by the organs will vary with the distribution of the blood cells in the organs, which in turn will depend on the predominance of the cell types labeled and their condition. 8 LABELING PROCEDURE Sterile technique must be used throughout. It is important that all equipment used for the preparation of reagents be thoroughly cleaned to assure the absence of trace metal impurities. The user should wear waterproof gloves during the handling and administration procedure. 1. The following equipment is recommended: One (1) 60 mL or two (2) 30 mL sterile disposable plastic syringes with a 19 or 20 gauge needle (NOTE: Do not use a smaller gauge needle). Ring stand and clamp(s). Three (3) 50 mL sterile conical plastic centrifuge tubes with screw caps. Label each set with patient ID and "WBC", "LPP" and "Wash" respectively (NOTE: 3 centrifuge tubes per patient). Clinical Centrifuge with horizontal, 4 place rotor or equivalent. Sodium Chloride 0.9% Injection, USP. Three (3) disposable 5 or 10 mL syringes and 19 gauge needles. Syringe shield to dispense indium In 111 oxyquinoline. A dose calibrator. Butterfly catheter infusion set. Test tube rack. Lab timer. 10 mL syringe with a 19 gauge or 20 gauge needle. 19 gauge needle with filter (optional). 2. Withdraw from the patient 30-50 mL blood [preferably fifty (50) mL] using aseptic venipuncture technique using the 60 mL syringe fitted with a 19 gauge or 20 gauge needle and containing approximately 1000-1500 units heparin in 1-2 mL. Blood withdrawal should be smooth and slow so as not to produce bubbles or foaming. 3. Remove and dispose of the needle and replace with a syringe cap. Gently mix the contents of the syringe and label with the patient's ID, date and time. 4. Upon receipt of the full syringe for processing, the contents should again be gently mixed. 5. Clamp the syringe barrel to the ring stand in an upright (needle side up) position and tilt the syringe 10-20 degrees from its position perpendicular to the bench. 6. Allow the red cells to sediment 30-60 minutes, depending upon when the supernatant [leukocyte rich plasma (LRP)] looks clear of red blood cells. 7. Replace the syringe cap with an infusion set. 8. Collect the plasma (LRP) in the centrifuge tube marked "WBC" by expressing the LRP through the catheter tubing making sure not to get any red cells into the WBC tube. 9. Immediately centrifuge the capped WBC tube at 400-450 g for 5 minutes. 9 10 Transfer the supernatant to the leukocyte poor plasma (LPP) tube leaving behind 0.5-1.0 mL supernatant to cover the white cell button (NOTE: the button often contains a small number of red cells and may appear red). 11. Wash the white cell button with 4-6 mL Sodium Chloride (0.9%) Injection, USP. Resuspend the button by gentle swirling. 12. Centrifuge the capped WBC tube at 400-450 g for 5 minutes (alternatively, 150 g for 8 minutes) and discard all but 0.5-1.0 mL of the supernate to cover the cells. 13. Add 5.0 mL Sodium Chloride (0.9%) Injection, USP. Resuspend the cells by gentle swirling. 14. With the shielded syringe, draw up approximately 22.2 MBq, 600 µCi indium In 111 oxyquinoline. Check the amount of radioactivity in a dose calibrator set for indium In 111 and record for labeling efficiency calculations. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. 15. In several additions, add the indium In 111 oxyquinoline to the WBC tube, gently swirling after each addition. 16. Set the lab timer for 15 minutes and allow the capped WBC tube to incubate. Swirl the cell preparation several times during the incubation. 17. With a sterile plastic syringe, add half of the saved LPP (or about 8 mL) from the LPP tube. Cap and gently swirl the contents of WBC tube to resuspend the cells. 18. Centrifuge the WBC tube at 450 g for 5 minutes (or 150 g for 8 minutes). Decant supernatant into the wash tube leaving behind about 0.5 mL of the supernate to cover the cells. 19. Assay the activity in the WBC tube and in the wash tube in a dose calibrator and record. 20. With a sterile plastic syringe add the remaining LPP to the cell button and gently resuspend by swirling. With a sterile syringe fitted with a 19 gauge needle, resuspend the cells by drawing the cells up into the syringe and expressing the suspension against the tube gently once or twice. Alternatively, draw up the cells into a syringe fitted with the filtered 19 gauge needle, and replace the needle with an unfiltered 19 or 20 gauge needle. 21. Reserve in the WBC tube a minimum amount of white cell suspension for a WBC count. A microscopic examination should also be completed to observe for clumping. Draw up the patient's dose (7.4 to 18.5 MBq, 200-500 µCi) and check the syringe in the dose calibrator. Record the measurement. QUALITY CONTROL It is generally advantageous to record any observations on cell abnormalities (e.g., cell clumping). A trypan blue exclusion test may also be performed. It is recommended that the preparation be used within one hour of labeling (See Precautions). 10 HOW SUPPLIED Indium In 111 oxyquinoline solution is supplied in a vial as a single use only product containing 37 MBq, 1.0 mCi in 1.0 mL aqueous solution at the calibration date stated on the label. Vials are packaged in individual lead shields. NDC 17156-021-01 The contents of the vial are radioactive and adequate shielding and handling precautions must be maintained. This preparation is approved for use by persons licensed by the Illinois Emergency Management Agency pursuant to 32 IL. Adm. Code Section 330.260(a) and 335.4010 or equivalent licenses of the Nuclear Regulatory Commission or an Agreement State. SPECIAL HANDLING AND STORAGE Indium In 111 oxyquinoline solution should be stored at room temperature (15-25°C, 59-77°F). Indium In 111 oxyquinoline labeled autologous leukocytes should preferably be reinjected within one hour of labeling. The labeled cells may be stored at room temperature (15-25°C, 59- 77°F) for up to three hours following completion of the cell labeling procedure. Reinjection of indium In 111 oxyquinoline labeled autologous leukocytes more than 5 hours after initial blood drawing is not recommended. Sterile technique must be used throughout the collection, labeling and re-injection procedures. Manufactured by: GE Healthcare, Medi-Physics, Inc. Arlington Heights, IL 60004 U.S.A. Customer Service: 1-800-292-8514 Professional Services: 1-800-654-0118 GE and the GE Monogram are trademarks of General Electric Company. © 2013 General Electric Company - All rights reserved. 43-8021 Revised June 2013	custom-source	2025-02-12T13:45:13.662684	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/pre96/019044Orig1s000lbl.pdf', 'application_number': 19044, 'submission_type': 'ORIG ', 'submission_number': 1}
11,426	RETIN-A® Cream Gel Liquid (tretinoin) For Topical Use Only Prescribing Information Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert- butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: Leave space for structure. Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted. Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN- A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does adjusted for total body surface area). Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic does adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see Dosage and Administration Section). Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions) How Supplied: RETIN-A (tretinoin) is supplied as: RETIN-A Cream NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0165-02 0.025% Cream 45g 0062-0175-12 0.05% Cream 20g 0062-0175-13 0.05% Cream 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g RETIN-A Gel NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0575-44 0.01% Gel 15g 0062-0575-46 0.01% Gel 45g 0062-0475-42 0.025% Gel 15g 0062-0475-45 0.025% Gel 45g RETIN-A Liquid NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0075-07 0.05% Liquid 28 mL Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN- A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RETIN-A® PATIENT INSTRUCTIONS Cream Gel Liquid (tretinoin) Acne Treatment For Topical Use Only IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU’RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOU DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. (Insert picture) • Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. • It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. • Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. • RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. • RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected are. Smooth gently into the skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area where treatment is not intended (such as corners of the mouth, eyes, and nose). • It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday. Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Markham Luke 6/10/02 11:40:52 AM Acting for Dr. Jonathan Wilkin, Division Director, DDDDP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.842431	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 19049, 'submission_type': 'SUPPL ', 'submission_number': 7}
11,427	RETIN-A® Cream Gel Liquid (tretinoin) For Topical Use Only Prescribing Information Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or 0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert- butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid and has the following structure: Leave space for structure. Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established. Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is noted. Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN- A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of local irritation warrants, patients should be directed to use the medication less frequently, discontinue use temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution because of possible interaction with tretinoin. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to “rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun. Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does adjusted for total body surface area). Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats, mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum human systemic does adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RETIN-A is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of therapy (see Dosage and Administration Section). Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient. Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of application increased when the patients become able to tolerate the treatment. Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue therapy. Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required before definite beneficial effects are seen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less frequent applications, or other dosage forms. Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be cleansed thoroughly before the medication is applied. (See Precautions) How Supplied: RETIN-A (tretinoin) is supplied as: RETIN-A Cream NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0165-01 0.025% Cream 20g 0062-0165-02 0.025% Cream 45g 0062-0175-12 0.05% Cream 20g 0062-0175-13 0.05% Cream 45g 0062-0275-23 0.1% Cream 20g 0062-0275-01 0.1% Cream 45g RETIN-A Gel NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0575-44 0.01% Gel 15g 0062-0575-46 0.01% Gel 45g 0062-0475-42 0.025% Gel 15g 0062-0475-45 0.025% Gel 45g RETIN-A Liquid NDC Code RETIN-A Strength/Form RETIN-A Qty. 0062-0075-07 0.05% Liquid 28 mL Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN- A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda RETIN-A® PATIENT INSTRUCTIONS Cream Gel Liquid (tretinoin) Acne Treatment For Topical Use Only IMPORTANT Read Directions Carefully Before Using THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY QUESTIONS, BE SURE TO ASK YOUR DOCTOR. WARNINGS RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C). PRECAUTIONS The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized. Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors. These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either laboratory animals or humans. However, investigations in this area are continuing. Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an SPF level which will provide you with the necessary high level of protection). For extended sun exposure, protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you do become sunburned, stop your therapy with RETIN-A until your skin has recovered. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your acne treatment under such conditions. Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your physician. There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when the skin was allowed to adjust to RETIN-A or therapy was discontinued. Use other medication only on your physician’s advice. Only your physician knows which other medications may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and hair permanent solutions. Do not allow anyone else to use this medication. Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you have used in the past might cause unnecessary redness or peeling. If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are nursing a baby, consult your physician before using the medication. AND WHILE YOU’RE ON RETIN-A THERAPY Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician, etc., may worsen your acne. HOW TO USE RETIN-A (TRETINOIN) To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN, FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF YOU HAVE QUESTIONS, ASK YOU DOCTOR. To help you use the medication correctly, keep these simple instructions in mind. (Insert picture) • Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise, especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First, wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation. • It is better not to use more than the amount suggested by your physician or to apply more frequently than instructed. Too much may irritate the skin, waste medication and won’t give faster or better results. • Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from these areas when applying. • RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth gently into the skin. • RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough for your whole face, after you have some experience with the medication you may find you need slightly more or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected are. Smooth gently into the skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear, spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area where treatment is not intended (such as corners of the mouth, eyes, and nose). • It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your acne (noncomedogenic) every morning after you wash. WHAT TO EXPECT WITH YOUR NEW TREATMENT RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient. There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their skin begins to take on a blush. These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully. Should the effects become excessively troublesome, consult your doctor. BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At this stage it is important to continue using RETIN-A. If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop treatment at the first signs of improvement. Once your acne is under control you should continue regular application of RETIN-A until your physician instructs otherwise. IF YOU HAVE QUESTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A (tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday through Friday. Ortho Dermatological (new logo) Division of Ortho-McNeil Pharmaceutical, Inc. Skillman, New Jersey 08558 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Markham Luke 6/10/02 11:40:52 AM Acting for Dr. Jonathan Wilkin, Division Director, DDDDP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:13.850762	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 19049, 'submission_type': 'SUPPL ', 'submission_number': 8}
11,429	Sufentanil Citrate Injection, USP CII Rx only DESCRIPTION Sufentanil Citrate Injection, USP is a potent opioid analgesic chemically designated as N-[4-(methyoxymethyl)-1 [2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide: 2-hydroxy-1,2,3-propanetricarboxylate (1:1) with a molecular weight of 578.68. The structural formula of Sufentanil Citrate is: structural formula Sufentanil Citrate Injection is a sterile, preservative free, aqueous solution containing sufentanil citrate equivalent to 50 mcg per mL of sufentanil base for intravenous and epidural injection. The solution has a pH range of 3.5 to 6.0. CLINICAL PHARMACOLOGY Pharmacology Sufentanil is an opioid analgesic. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl. Assays of histamine in patients administered sufentanil citrate have shown no elevation in plasma histamine levels and no indication of histamine release. (See dosage chart for more complete information on the intravenous use of Sufentanil Citrate Injection.) Pharmacodynamics Intravenous use At intravenous doses of up to 8 mcg/kg, sufentanil is an analgesic component of general anesthesia; at intravenous doses ≥8 mcg/kg, sufentanil produces a deep level of anesthesia. Sufentanil produces a dose related attenuation of catecholamine release, particularly norepinephrine. At intravenous dosages of ≥8 mcg/kg, sufentanil produces hypnosis and anesthesia without the use of additional anesthetic agents. A deep level of anesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/kg attenuate the sympathetic response to surgical stress. The catecholamine response, particularly norepinephrine, is further attenuated at doses of sufentanil of 25 to 30 mcg/kg, with hemodynamic stability and preservation of favorable myocardial oxygen balance. Sufentanil has an immediate onset of action, with relatively limited accumulation. Rapid elimination from tissue storage sites allows for relatively more rapid recovery as compared with equipotent dosages of fentanyl. At dosages of 1 to 2 mcg/kg, recovery times are comparable to those observed with fentanyl; at dosages of >2 to 6 mcg/kg, recovery times are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic dosage range of 8 to 30 Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mcg/kg of sufentanil, recovery times are more rapid compared to equipotent fentanyl dosages. The vagolytic effects of pancuronium may produce a dose dependent elevation in heart rate during sufentanil oxygen anesthesia. The use of moderate doses of pancuronium or of a less vagolytic neuromuscular blocking agent may be used to maintain a stable lower heart rate and blood pressure during sufentanil-oxygen anesthesia. The vagolytic effects of pancuronium may be reduced in patients administered nitrous oxide with sufentanil. Preliminary data suggest that in patients administered high doses of sufentanil, initial dosage requirements for neuromuscular blocking agents are generally lower as compared to patients given fentanyl or halothane, and comparable to patients given enflurane. Bradycardia is infrequently seen in patients administered sufentanil-oxygen anesthesia. The use of nitrous oxide with high doses of sufentanil may decrease mean arterial pressure, heart rate and cardiac output. Sufentanil at 20 mcg/kg has been shown to provide more adequate reduction in intracranial volume than equivalent doses of fentanyl, based upon requirements for furosemide and anesthesia supplementation in one study of patients undergoing craniotomy. During carotid endarterectomy, sufentanil-nitrous oxide/oxygen produced reductions in cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen. During cardiovascular surgery, sufentanil-oxygen produced EEG patterns similar to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate general anesthesia. The intraoperative use of sufentanil at anesthetic dosages maintains cardiac output, with a slight reduction in systemic vascular resistance during the initial postoperative period. The incidence of postoperative hypertension, need for vasoactive agents and requirements for postoperative analgesics are generally reduced in patients administered moderate or high doses of sufentanil as compared to patients given inhalation agents. Skeletal muscle rigidity is related to the dose and speed of administration of sufentanil. This muscular rigidity may occur unless preventative measures are taken (see WARNINGS). Decreased respiratory drive and increased airway resistance occur with sufentanil. The duration and degree of respiratory depression are dose related when sufentanil is used at sub-anesthetic dosages. At high doses, a pronounced decrease in pulmonary exchange and apnea may be produced. Epidural use in Labor and Delivery Onset of analgesic effect occurs within approximately 10 minutes of administration of epidural doses of sufenatnil and bupivacaine. Duration of analgesia following a single epidural injection of 10 to 15 mcg sufentanil and bupivacaine 0.125% averaged 1.7 hours. During labor and vaginal delivery, the addition of 10 to 15 mcg sufentanil to 10 mL 0.125% bupivacaine provides an increase in the duration of analgesia compared to bupivacaine without an opioid. Analgesia from 15 mcg sufentanil plus 10 mL 0.125% bupivacaine is comparable to analgesia from 10 mL of 0.25% bupivacaine alone. Apgar scores of neonates following epidural administration of both drugs to women in labor were comparable to neonates whose mothers received bupivacaine without an opioid epidurally. Pharmacokinetics Intravenous use The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and elimination half-life of 164 minutes in adults. The elimination half-life of sufentanil is shorter (e.g. 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g. 434 +/- 160 minutes) compared to that of adolescents and adults. The liver and small intestine are the major sites of biotransformation. Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Epidural use in Labor and Delivery After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. CLINICAL STUDIES Epidural use in Labor and Delivery Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself. Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes. There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g. after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours. INDICATIONS AND USAGE Sufentanil Citrate Injection is indicated for intravenous administration in adults and pediatric patients: as an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated. as a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, in patients who are intubated and ventilated, such as cardiovascular surgery or neurosurgical procedures in the sitting position, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated. Sufentanil Citrate Injection is indicated for epidural administration as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine during labor and vaginal delivery. SEE DOSAGE AND ADMINISTRATION SECTION FOR MORE COMPLETE INFORMATION ON THE USE OF SUFENTANIL. CONTRAINDICATIONS Sufentanil Citrate Injection is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists. WARNINGS SUFENTANIL CITRATE INJECTION SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS AND EPIDURAL ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS. AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE. PRIOR TO CATHETER INSERTION, THE PHYSICIAN SHOULD BE FAMILIAR WITH PATIENT CONDITIONS (SUCH AS INFECTION AT THE INJECTION SITE, BLEEDING DIATHESIS, ANTICOAGULANT THERAPY, ETC.) WHICH CALL FOR SPECIAL EVALUATION OF THE BENEFIT VERSUS RISK POTENTIAL. Intravenous use Intravenous administration or unintentional intravascular injection during epidural administration of sufentanil citrate may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is dose related. Administration of sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. As with fentanyl, muscular rigidity has been reported to occur or recur infrequently in the extended postoperative period. The incidence of muscular rigidity associated with intravenous sufentanil can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda prior to administration of sufentanil at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of sufentanil and a full paralyzing dose of a neuromuscular blocking agent when sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg). The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. PRECAUTIONS General: The initial dose of sufentanil should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses. Vital signs should be monitored routinely. Nitrous oxide may produce cardiovascular depression when given with high doses of sufentanil (see CLINICAL PHARMACOLOGY). Bradycardia has been reported infrequently with sufentanil-oxygen anesthesia and has been responsive to atropine. Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by sufentanil may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the postoperative period. Respiratory depression may be enhanced when sufentanil is administered in combination with volatile inhalational agents and/or other central nervous system depressants such as barbiturates, tranquilizers, and other opioids. Appropriate postoperative monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained prior to discharging the patient from the recovery area. Respiration should be closely monitored following each administration of an epidural injection of sufentanil. Proper placement of the needle or catheter in the epidural space should be verified before sufentanil is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil/bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Sufentanil should be administered epidurally by slow injection. Neuromuscular Blocking Agents: The hemodynamic effects and degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. High doses of pancuronium may produce increases in heart rate during sufentanil-oxygen anesthesia. Bradycardia and hypotension have been reported with other muscle relaxants during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of calcium channel and/or beta-blockers. Muscle relaxants with no clinically significant effect on heart rate (at recommended doses) would not counteract the vagotonic effect of sufentanil, therefore a lower heart rate would be expected. Rare reports of bradycardia associated with the concomitant use of succinylcholine and sufentanil have been reported. Interaction with Calcium Channel and Beta Blockers: The incidence and degree of bradycardia and hypotension during induction with sufentanil may be greater in patients on chronic calcium channel and beta blocker therapy. (See Neuromuscular Blocking Agents.) Interaction with Other Central Nervous System Depressants: Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when sufentanil is administered to patients receiving barbiturates, tranquilizers, other opioids, general anesthetic or other CNS depressants. In such cases of combined treatment, the dose of sufentanil and/or these agents should be reduced. The use of benzodiazepines with sufentanil during induction may result in a decrease in mean arterial pressure and systemic vascular resistance. Head Injuries: Sufentanil may obscure the clinical course of patients with head injuries. Impaired Respiration: Sufentanil should be used with caution in patients with pulmonary disease, decreased Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration. Impaired Hepatic or Renal Function: In patients with liver or kidney dysfunction, sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of sufentanil. Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis: Long-term animal studies have not been performed to evaluate the carcinogenic potential of sufentanil. Mutagenesis: Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay. Impairment of fertility: Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rated were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity. Pregnancy Category C There are no adequate and well-controlled trials of sufentanil in pregnant women. Sufentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Embryolethality and maternal toxicity were noted in rabbits treated from Gestation Day 6 to 18 with 0.08 mg/kg sufentanil IV (0.9 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison). No teratogenic effects were observed in either rats or rabbits at these exposures. In a pre- and post-natal development study in rats, sufentanil doses of 0.02 and 0.08 mg/kg decreased pup weight and survival at maternally toxic doses (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison). Labor and Delivery The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections.) Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume). Nursing Mothers It is not known whether sufentanil is excreted in human milk. Because fentanyl analogs are excreted in human milk, caution should be exercised when sufentanil citrate is administered to a nursing woman. Pediatric Use The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug. ADVERSE REACTIONS The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS on the management of respiratory depression and skeletal muscle rigidity. Urinary retention has been associated with the use of epidural opioids but was not reported in the clinical trials of epidurally administered sufentanil due to the use of indwelling Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda catheters. The incidence of urinary retention in patients without urinary catheters receiving epidural sufentanil is unknown; return of normal bladder activity may be delayed. The following adverse reaction information is derived from controlled clinical trials in 320 patients who received intravenous sufentanil during surgical anesthesia and in 340 patients who received epidural sufentanil plus bupivacaine 0.125% for analgesia during labor and is presented below. Based on the observed frequency, none of the reactions occurring with an incidence less than 1% were observed during clinical trials of epidural sufentanil used during labor and delivery (N=340). In general cardiovascular and musculoskeletal adverse experiences were not observed in clinical trials of epidural sufentanil. Hypotension was observed 7 times more frequently in intravenous trials than in epidural trials. The incidence of central nervous system, dermatological and gastrointestinal adverse experiences was approximately 4 to 25 times higher in studies of epidural use in labor and delivery. Probably Causally Related: Incidence Greater than 1% - Derived from clinical trials (See preceding paragraph) Cardiovascular: bradycardia, hypertension, hypotension. Musculoskeletal: chest wall rigidity. Central Nervous System: somnolence. Dermatological: pruritus (25%). Gastrointestinal: nausea, vomiting. Incidence 3% to 9% Probably Causally Related: Incidence Less than 1% - Derived from clinical trials (Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized.) Body as a whole: anaphylaxis. Cardiovascular: arrhythmia, tachycardia, cardiac arrest. Central Nervous System: chills. Dermatological: erythema. Musculoskeletal: skeletal muscle rigidity of neck and extremities. Respiratory: apnea, bronchospasm, postoperative respiratory depression. Miscellaneous: intraoperative muscle movement. *Incidence 0.3% to 1% DRUG ABUSE AND DEPENDENCE Sufentanil Citrate Injecton is a Schedule II controlled drug product that can produce drug dependence of the morphine type and therefore has the potential for being abused. OVERDOSAGE Overdosage is manifested by an extension of the pharmacological actions of sufentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. The most serious and significant effect of overdose for both intravenous and epidural administration of sufentanil is respiratory depression. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with sufentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude more immediate countermeasures. In the event of overdosage, oxygen should be administered and ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent airway must be maintained, and a nasopharyngeal airway or endotracheal tube may be indicated. If depressed respiration is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed. DOSAGE AND ADMINISTRATION Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The dosage of sufentanil should be individualized in each case according to body weight, physical status, underlying pathological condition, use of other drugs, and type of surgical procedure and anesthesia. In obese patients (more than 20% above ideal total body weight), the dosage of sufentanil should be determined on the basis of lean body weight. Dosage should be reduced in elderly and debilitated patients (see PRECAUTIONS). Vital signs should be monitored routinely. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Because the clearance of sufentanil is reduced in neonates, especially those with cardiovascular disease, the dose of sufentanil should be reduced accordingly (see PRECAUTIONS). Intravenous use Sufentanil Citrate may be administered intravenously by slow injection or infusion 1) in doses of up to 8 mcg/kg as an analgesic adjunct to general anesthesia, and 2) in doses ≥8 mcg/kg as a primary anesthetic agent for induction and maintenance of anesthesia (see Dosage Range Chart). If benzodiazepines, barbiturates, inhalation agents, other opioids or other central nervous system depressants are used concomitantly, the dose of sufentanil and/or these agents should be reduced (see PRECAUTIONS). In all cases dosage should be titrated to individual patient response. Usage in Children: For induction and maintenance of anesthesia in children less than 12 years of age undergoing cardiovascular surgery, an anesthetic dose of 10 to 25 mcg/kg administered with 100% oxygen is generally recommended. Supplemental dosages of up to 25 to 50 mcg are recommended for maintenance, based on response to initial dose and as determined by changes in vital signs indicating surgical stress or lightening of anesthesia. Premedication: The selection of preanesthetic medications should be based upon the needs of the individual patient. Neuromuscular Blocking Agents: The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS). ADULT DOSAGE RANGE CHART for Intravenous use ANALGESIC COMPONENT TO GENERAL ANESTHESIA •TOTAL DOSAGE REQUIREMENTS OF 1 MCG/KG/HR OR LESS ARE RECOMMENDED TOTAL DOSAGE MAINTENANCE DOSAGE ANALGESIC DOSAGES Incremental or Infusion: 1 to 2 mcg/kg (expected duration of Incremental: 10 to 25 mcg (0.2 to 0.5 mL) may be administered in anesthesia 1 to 2 hours). Approximately 75% or more of total increments as needed when movement and/or changes in vital signs sufentanil dosage may be administered prior to intubation by either indicate surgical stress or lightening of analgesia. Supplemental dosages slow injection or infusion titrated to individual patient response. should be individualized and adjusted to remaining operative time Dosages in this range are generally administered with nitrous anticipated. oxide/oxygen in patients undergoing general surgery in which Infusion: Sufentanil citrate may be administered as an intermittent or endotracheal intubation and mechanical ventilation are required. continuous infusion as needed in response to signs of lightening of analgesia. In absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. Dosage should be individualized and adjusted to remaining operative time anticipated. ANALGESIC DOSAGES Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incremental or Infusion: 2 to 8 mcg/kg (expected duration of anesthesia 2 to 8 hours). Approximately 75% or less of the total calculated sufentanil dosage may be administered by slow injection or infusion prior to intubation, titrated to individual patient response. Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures in which endotracheal intubation and mechanical ventilation are required. At dosages in this range, sufentanil has been shown to provide some attenuation of sympathetic reflex activity in response to surgical stimuli, provide hemodynamic stability, and provide relatively rapid recovery. ANESTHETIC DOSAGES Incremental or Infusion: 8 to 30 mcg/kg (anesthetic doses). At this anesthetic dosage range sufentanil is generally administered as a slow injection, as an infusion, or as an injection followed by an infusion. sufentanil with 100% oxygen and a muscle relaxant has been found to produce sleep at dosages ≥8 mcg/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents. The addition of N2O to these dosages will reduce systolic blood pressure. At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated. Dosages of 25 to 30 mcg/kg have been shown to block sympathetic response including catecholamine release. High doses are indicated in patients undergoing major surgical procedures, in which endotracheal intubation and mechanical ventilation are required, such as cardiovascular surgery and neurosurgery in the sitting position with maintenance of favorable myocardial and cerebral oxygen balance. Postoperative observation is essential and postoperative mechanical ventilation may be required at the higher dosage range due to extended postoperative respiratory depression. Dosage should be titrated to individual patient response. Incremental: 10 to 50 mcg (0.2 to 1 mL) may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated. Infusion: Sufentanil citrate may be administered as an intermittent or continuous infusion as needed in response to signs of lightening of analgesia. In the absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. Dosage should be individualized and adjusted to remaining operative time anticipated. Incremental: Depending on the initial dose, maintenance doses of 0.5 to 10 mcg/kg may be administered by slow injection in anticipation of surgical stress such as incision, sternotomy or cardiopulmonary bypass. Infusion: Sufentanil citrate may be administered by continuous or intermittent infusion as needed in response to signs of lightening of anesthesia. In the absence of lightening of anesthesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. The maintenance infusion rate for sufentanil should be based upon the induction dose so that the total dose for the procedure does not exceed 30 mcg/kg. In patients administered high doses of sufentanil, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression. Also see WARNINGS and PRECAUTIONS sections. For purposes of administering small volumes of Sufentanil Citrate Injection accurately, the use of a tuberculin syringe or equivalent is recommended. Epidural use in Labor and Delivery Proper placement of the needle or catheter in the epidural space should be verified before sufentanil citrate is injected to assure that unintentional intravas- cular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil, bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Sufentanil should be administered by slow injection. Respiration should be closely monitored following each administration of an epidural injection of sufentanil. Dosage for Labor and Delivery: The recommended dosage is sufentanil 10 to 15 mcg administered with 10 mL bupivacaine 0.125% with or without epinephrine. Sufentanil and bupivacaine should be mixed together before administration. Doses can be repeated twice (for a total of three doses) at not less than one-hour intervals until delivery. HOW SUPPLIED Sufentanil Citrate Injection, USP is supplied as a sterile aqueous preservative-free solution for intravenous and epidural use as: NDC 17478-050-01 50 mcg/mL sufentanil base, 1 mL ampules in packages of 10 NDC 17478-050-02 50 mcg/mL sufentanil base, 2 mL ampules in packages of 10 NDC 17478-050-05 50 mcg/mL sufentanil base, 5 mL ampules in packages of 10 Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda STORAGE: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. PROTECT FROM LIGHT. U.S. Patent No. 3,998,834 MAY 1995, SEPTEMBER 1995 company logo Manufactured by: Akorn, Inc. Lake Forest, IL 60045 SFA0N Rev. 02/14 Reference ID: 3474389 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:14.279562	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019050s032lbl.pdf', 'application_number': 19050, 'submission_type': 'SUPPL ', 'submission_number': 32}
11,425	NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 4 Baxter OSMITROL Injection (Mannitol Injection, USP) in AVIVA Plastic Container For Therapeutic Use Only Description Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. Composition, osmolarity, and pH are shown in Table 1. Composition Table 1 Size (mL) Mannitol, USP (g/L) Osmolarity (mOsmol/L) (calc) pH 5% OSMITROL Injection (5% Mannitol Injection, USP) 1000 50 274 5.5 (4.5 TO 7.0) 500 10% OSMITROL Injection (10% Mannitol Injection, USP) 1000 100 549 5.5 (4.5 TO 7.0) 15% OSMITROL Injection (15% Mannitol Injection, USP) 500 150 823 5.5 (4.5 TO 7.0) 250 20% OSMITROL Injection (20% Mannitol Injection, USP) 500 200 1098 5.5 (4.5 TO 7.0) Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L. Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 5 Mannitol The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for the attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not secreted by the tubule, and is pharmacologically inert. Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 6 and chloride by elevating the osmolarity of the glomerular filtrate. This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure. Indications and Usage Osmitrol Injection (Mannitol Injection, USP) is indicated for: The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established; The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass; The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means, and promoting the urinary excretion of toxic substances. Contraindications Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with: Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal damage or dysfunction after institution of mannitol therapy, including increasing oliguria and azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy. Warnings In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and Administration). A second test dose may be tried if there is an inadequate response, but no more than two test doses should be attempted. The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration. If urine output continues to decline during mannitol infusion, the patient’s clinical status should be closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart failure. Excessive loss of water and electrolytes may lead to serious imbalances. With continued administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte measurements, including sodium and potassium, are therefore, of vital importance in monitoring the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 7 infusion of mannitol. Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during mannitol infusion. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. The cardiovascular status of the patient should be carefully evaluated before rapidly administrating mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia. By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolemia. Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool to room temperature before reinspection for crystals. Administer intravenously using sterile, filter- type administration set. Laboratory Tests Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 8 The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring. Drug Interaction Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol Injection (Mannitol Injection, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also not known whether mannitol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. Usage in Children Dosage requirements for patients 12 years of age and under have not been established. Geriatric Use Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 9 to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Extensive use of mannitol over the last several decades has produced recorded adverse events, in a variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions have occurred with any great frequency nor with any security in attributing them to mannitol. The inability to clearly exclude the drug related nature of such events in these isolated reports prompts the necessity to list the reactions that have been observed in patients during or following mannitol infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension, tachycardia, fever and angina-like chest pains. Of far greater clinical significance is a variety of events that are related to inappropriate recognition and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner. Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or aggravate preexisting hyponatremia. If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred vision, convulsions and congestive cardiac failure. These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of degree of renal failure with a test dose response to mannitol when indicated; evaluation of hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration; and evaluation of renal, cardiac and pulmonary function at the onset of therapy. Dosage and Administration Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion. The total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 10 and dosage is only a general guide to therapy. Parenteral dug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20% solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if there is an inadequate response, the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will depend upon the fluid requirements of the patient. Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20% solution. Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a prompt and maximal effect. When used preoperatively the dose should be given one to one and one- half hours before surgery to achieve maximal reduction of intraocular pressure before operation. Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a satisfactory reduction in intracranial pressure. Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15% or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary output of the patient. Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of dosage. All injections in AVIVA containers are intended for intravenous administration using sterile equipment. The use of supplemental additive medication is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 11 How Supplied Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows: Code Size (mL) NDC Product Name 6E5604 1000 0338-6300-04 5% Osmitrol Injection (5% Mannitol Injection, USP) 6E5613 6E5614 500 1000 0338-6301-03 0338-6301-04 10% Osmitrol Injection (10% Mannitol Injection, USP) 6E5623 500 0338-6302-03 15% Osmitrol Injection (15% Mannitol Injection, USP) 6E5632 6E5633 250 500 0338-6303-02 0338-6303-03 20% Osmitrol Injection (20% Osmitrol Injection) Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 12 ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 13 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 14 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 15 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 16 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 17 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 18 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 19 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 20 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 21 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 22 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 23 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 24 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 25 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). c * D-Glucopyranose monohydrate Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 26 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 27 electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 28 Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum amorality and possible hemorrhage. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 29 reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasations, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size NDC 6E2073 500 mL NDC 0338-6306-03 6E2074 1000 mL NDC 0338-6306-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 30 To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 31 All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 32 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2·2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 250 500 Lactated Ringer’s Injection, USP 1000 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 33 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the treatment of lactic acidosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 34 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Test CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH EVALUATION. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's Injection, USP. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 35 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis; periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of infection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 36 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 37 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 38 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 39 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 40 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 41 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 42 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 43 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 44 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 45 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 46 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 47 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 48 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 49 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 50 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 51 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 52 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 53 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 54 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 55 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 56 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 57 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 58 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 59 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA Plastic Container Description Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Lactate (C3H5NaO3) Osmolarity (mOsmol/L) (calc) pH Sodium Lactate Caloric Content (kcal/L) 500 Sodium Lactate Injection, USP (M/6 Sodium Lactate) 1000 18.7 334 6.5 (6.0 to 7.3) 167 167 54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 60 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications None known Warnings Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result in sodium retention. Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis. Precautions General This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 61 Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium Lactate) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Lactate Injection, USP (M/6 Sodium Lactate). Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6 Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 62 Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 63 How Supplied Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E1803 500 0338-6311-03 6E1804 1000 0338-6311-04 EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 64 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 65 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 66 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 67 edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 68 Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 69 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 70 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 71 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 72 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 73 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 74 Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 75 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 76 Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 77 Baxter Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no antimicrobial agents. The pH is 4.0 (3.5 to 6.5). c D-Glucopyranose monohydrate Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium, 4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 78 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 79 Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5% Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is administered to a nursing woman. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 80 Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of ringer's and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 81 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2064 1000 NDC 0338-6313-04 6E2063 500 NDC 0338-6313-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 82 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter Healthcare International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 83 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 84 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 85 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 86 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 87 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 88 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 89 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 90 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 91 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 92 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 93 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 94 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 95 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 96 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 97 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 98 Clinical Pharmacology PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 99 In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 100 Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 101 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2534 1000 NDC 0338-6316-04 6E2533 500 NDC 0338-6316-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 102 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 103 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 lcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 104 Clinical Pharmacology PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 105 overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 106 A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elkerly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 107 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2544 1000 NDC 0338-6317-04 6E2543 500 NDC 0338-6317-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 108 To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 109 Baxter PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 110 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 111 PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 112 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 113 selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 114 6E2573 500 NDC 0338-6318-03 6E2574 1000 NDC 0338-6318-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 115 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 116 Baxter PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate (C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 117 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 118 administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium ions may result in sodium or potassium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 119 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 120 In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 121 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2564 NDC 0338-6319-04 500 6E2563 NDC 0338-6319-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 122 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 123 Baxter PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl); 89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 124 PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 125 Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA- LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 126 Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 127 Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2504 1000 NDC 0338-6320-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 128 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 129 Baxter PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 130 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 131 The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 132 Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 133 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2584 NDC 0338-6321-04 500 6E2583 NDC 0338-6321-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 134 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 135 XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 136 Baxter 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and 12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq chloride, 23 mEq lactate and 3 mEq phosphate as HPO4 =. The osmolarity is 348 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 137 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 138 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not administer simultaneously with blood. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 139 Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemmorhage. Geriatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 140 Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 141 How Supplied 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2102 250 NDC 0338-6322-02 6E2103 500 NDC 0338-6322-03 6E2104 1000 NDC 0338-6322-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 142 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 143 Baxter Potassium Chloride in 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. HO O OH • H O OH OH HO 2 * D-Glucose monohydrate Composition (g/L) Ionic Concentration (mEq/L) Table 1 Potassium Chloride in 5% Dextrose Injection, USP mEq Potassium Size (mL) *Dextrose Hydrous, USP Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Potassium Chloride Caloric Content (kcal/L) 10 mEq 1000 50 0.75 272 4.5 (3.5 to 6.5) 10 10 170 20 mEq 1000 50 1.5 293 4.5 (3.5 to 6.5) 20 20 170 30 mEq 1000 50 2.24 312 4.5 (3.5 to 6.5) 30 30 170 40 mEq 1000 20 mEq 500 50 3 333 4.5 (3.5 to 6.5) 40 40 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 144 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwarp is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not administer simultaneously with blood. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 145 The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose Injection, USP may result in potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose Injection, USP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 146 Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 147 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1124 1000 0338-6323-04 10 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1134 1000 0338-6324-04 20 mEq Potassium Chloride in 5% Dextrose Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 148 6E1174 1000 0338-6325-04 30 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1264 1000 0338-6326-04 40 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1263 500 0338-6326-03 20 mEq Potassium Chloride in 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 149 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 150 Baxter Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid and electrolyte replenishment in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (Calc.) pH Sodium Potassium Chloride 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 1.5 348 5.5 (3.5 to 6.5) 154 20 174 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 3 388 5.5 (3.5 to 6.5) 154 40 194 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 151 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride Injection, USP may result in sodium or potassium retention. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 152 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 153 Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Geriatric Use Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 154 Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1764 1000 0338-6327-04 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 6E1984 1000 0338-6328-04 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C (104º F) does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 155 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 156 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 157 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 158 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 159 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 160 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 161 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 162 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 163 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 164 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 165 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 166 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 167 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 168 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 169 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 170 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 171 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 172 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 173 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 174 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 175 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 176 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 177 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 178 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 179 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 180 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 181 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 182 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 183 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 184 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 185 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 186 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 187 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 188 Baxter 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate, and 15 mEq phosphate as HPO4 =. The osmolarity is 402 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 189 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen, and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 190 dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overloading causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 191 Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION (MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING MOTHER. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 192 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2112 250 NDC 0338-6338-02 6E2113 500 NDC 0338-6338-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 193 6E2114 1000 NDC 0338-6338-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 194 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 195 Baxter 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container Description 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 size (mL) Sodium Chloride USP (NaCl) Sodium Chloride Osmolarity (mOsmol/L) (calc) pH 3% Sodium Chloride Injection, USP 500 30 513 513 1027 5.5 (4.5 to 7.0) 5% Sodium Chloride Injection, USP 500 50 856 856 1711 5.5 (4.5 to 7.0) Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 196 Clinical Pharmacology 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings 3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage. 3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 197 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3% and 5% Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5% Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 198 Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1353 500 0338-6339-03 3% Sodium Chloride Injection, USP 6E1373 500 0338-6340-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 199 Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 200 Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 201 Baxter PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic, hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains 234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 202 PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of hemolysis. The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 203 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 204 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 205 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2524 1000 NDC 0338-6341-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 206 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 207 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Composition (g/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc.) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 208 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Ionic Concentration (mEq/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 ** The chemical structure for Dextrose Hydrous, USP is shown below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 209 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn product. Warnings Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 210 congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the treatment of lactic acidosis. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 211 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly neonates and low birth weight infants. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 212 from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of fall parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC Product Name 6E2224 1000 NDC 0338-6344-04 20 mEq/L Potassium Chloride in Lactated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 213 Ringer’s and 5% Dextrose Injection, USP 6E2244 1000 NDC 0338-6345-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 214 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:14.573252	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 19047, 'submission_type': 'SUPPL ', 'submission_number': 24}
11,428	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Ampules (5 mL each) LOT EXP. For your convenience in recording narcotic use INITIAL/DATE 1 2 3 4 5 6 7 8 9 10 SFAEC Rev. 12/06 6505-01-193-2690 NDC 11098-050-05 10 Ampules (5 mL each) 10 Ampules (5 mL each) 5mL FOR INTRAVENOUS AND EPIDURAL USE Not to be sold except as an unbroken box. only SUFENTA® (SUFENTANIL CITRATE INJECTION, USP) SUFENTA® (SUFENTANIL CITRATE INJECTION, USP) SUFENTA® (SUFENTANIL CITRATE INJECTION, USP) SUFENTA® (SUFENTANIL CITRATE INJECTION, USP) Each mL contains: Sufentanil base 50 mcg/mL. Warning - May be habit forming. Usual Dosage: See package insert for dosage and other information. Storage: Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature]. Protect from light. 5mL SUFENTA® (SUFENTANIL CITRATE INJECTION, USP) 50 mcg/mL 250 mcg/5mL Preservative Free This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. current labeling information, please visit https://www.fda.gov/drugsa abel may not be the latest approved by g information, please visit https://www. This label may not be the latest approved by FDA. current labeling information, please visit https://www.fda.gov/drugsa	custom-source	2025-02-12T13:45:14.765400	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019050s031lbl.pdf', 'application_number': 19050, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,430	DN1075V1 CR 25-003537 August 22, 2005 Page 1 of 22 (Nos. 3805, 3806, 3807, 3808) NEW HYTRIN® (terazosin hydrochloride) Capsules DESCRIPTION HYTRIN (terazosin hydrochloride), an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name and structural formula: (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2- furanyl)carbonyl]-, monohydrochloride, dihydrate. Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has a molecular weight of 459.93. HYTRIN capsules (terazosin hydrochloride capsules) for oral ingestion are supplied in four dosage strengths containing terazosin hydrochloride equivalent to 1 mg, 2 mg, 5 mg, or 10 mg of terazosin. Inactive Ingredients: 1 mg capsules: gelatin, glycerin, iron oxide, methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin. 2 mg capsules: D&C yellow No. 10, gelatin, glycerin, methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin. 5 mg capsules: D&C red No. 28, FD&C red No. 40, gelatin, glycerin, methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin. 10 mg capsules: FD&C blue No. 1, gelatin, glycerin, methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin. CLINICAL PHARMACOLOGY Pharmacodynamics: A. Benign Prostatic Hyperplasia (BPH) The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: a static component and a dynamic component. The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 2 of 22 size of the prostate does not correlate with the severity of BPH symptoms or the degree of urinary obstruction. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-l adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-l adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-l adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. Terazosin has been studied in 1222 men with symptomatic BPH. In three placebo-controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0-3, for a total score of 27 points. Results from these studies indicated that terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows: Symptom Score (Range 0-27) Peak Flow Rate (mL/sec) Mean Mean Mean Mean N Baseline Change (%) N Baseline Change (%) Study 1 (10mg)a Titration to fixed dose (12 wks) Placebo 55 9.7 -2.3 (24) 54 10.1 +1.0 (10) Terazosin 54 10.1 -4.5 (45)* 52 8.8 +3.0 (34)* Study 2 (2, 5, 10, 20 mg)b Titration to response (24 wks) Placebo 89 12.5 -3.8 (30) 88 8.8 +1.4 (16) Terazosin 85 12.2 -5.3 (43)* 84 8.4 +2.9 (35)* Study 3 (1, 2, 5, 10 mg)c Titration to response (24 wks) Placebo 74 10.4 -1.1 (11) 74 8.8 +1.2 (14) Terazosin 73 10.9 -4.6 (42)* 73 8.6 +2.6 (30)* a Highest dose 10 mg shown. b 23% of patients on 10 mg, 41% of patients on 20 mg. c 67% of patients on 10 mg. * Significantly (p≤ 0.05) more improvement than placebo. In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with terazosin from week 2 (or the first clinic visit) and throughout the study duration. Analysis of the effect of terazosin on individual urinary symptoms demonstrated that compared to placebo, terazosin significantly improved the symptoms of hesitancy, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 3 of 22 intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia. Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. In studies 1 and 3, patients treated with terazosin had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. In a short term study (Study 1), patients were randomized to either 2, 5 or 10 mg of terazosin or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo (Figure 1). Figure 1 Study 1 Mean Change in Total Symptom Mean Increase in Peak Flow Score from Baseline+ Rate (mL/sec) from Baseline+ + for baseline values see above table * p ≤ 0.05, compared to placebo group In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3): Figure 2 Mean Change in Total Symptom Score from Baseline Long-Term, Open-Label, Non-Placebo Controlled Study (N=494) * p ≤ 0.05 vs. baseline mean baseline = 10.7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 4 of 22 Figure 3 Mean Change in Peak Flow Rate from Baseline Long-Term, Open-Label, Non-Placebo Controlled Study (N=494) * p ≤ 0.05 vs. baseline mean baseline = 9.9 In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect: Mean Changes in Blood Pressure from Baseline to Final Visit in all Double-Blind, Placebo-Controlled Studies Normotensive Patients DBP ≤ 90 mm Hg Hypertensive Patients DBP > 90 mm Hg Group N Mean Change N Mean Change SBP Placebo 293 -0.1 45 -5.8 (mm Hg) Terazosin 519 -3.3* 65 -14.4* DBP Placebo 293 +0.4 45 -7.1 (mm Hg) Terazosin 519 -2.2* 65 -15.1* * p ≤ 0.05 vs. placebo B. Hypertension In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. Terazosin decreases blood pressure gradually within 15 minutes following oral administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 5 of 22 Patients in clinical trials of terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5-20 mg/day, and had mild (about 77%, diastolic pressure 95-105 mmHg) or moderate (23%, diastolic pressure 105-115 mmHg) hypertension. Because terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). Blood pressure responses were measured at the end of the dosing interval (usually 24 hours) and effects were shown to persist throughout the interval, with the usual supine responses 5-10 mmHg systolic and 3.5-8 mmHg diastolic greater than placebo. The responses in the standing position tended to be somewhat larger, by 1-3 mmHg, although this was not true in all studies. The magnitude of the blood pressure responses was similar to prazosin and less than hydrochlorothiazide (in a single study of hypertensive patients). In measurements 24 hours after dosing, heart rate was unchanged. Limited measurements of peak response (2-3 hours after dosing) during chronic terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5-20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-related side effects, such as dizziness, palpitations, or orthostatic complaints, are seen within a few hours after dosing. The greater blood pressure effect associated with peak plasma concentrations (first few hours after dosing) appears somewhat more position-dependent (greater in the erect position) than the effect of terazosin at 24 hours and in the erect position there is also a 6-10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg, compared to 4% of a placebo group. There was a tendency for patients to gain weight during terazosin therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin gained a mean of 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2 pounds respectively in the placebo group. Both differences were statistically significant. During controlled clinical trials, patients receiving terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 6 of 22 Analysis of clinical laboratory data following administration of terazosin suggested the possibility of hemodilution based on decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin. Decreases in hematocrit and total protein have been observed with alpha-blockade and are attributed to hemodilution. Pharmacokinetics: Terazosin hydrochloride administered as HYTRIN capsules is essentially completely absorbed in man. Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14.0 and 11.4 hours for the age group ≥ 70 years and the age group of 20-39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20-39 years of age. The drug is 90-94% bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man. INDICATIONS AND USAGE HYTRIN (terazosin hydrochloride) is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH). There is a rapid response, with approximately 70% of patients experiencing an increase in urinary flow and improvement in symptoms of BPH when treated with HYTRIN. The long-term effects of HYTRIN on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined. HYTRIN is also indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive agents such as diuretics or beta-adrenergic blocking agents. CONTRAINDICATIONS HYTRIN capsules are contraindicated in patients known to be hypersensitive to terazosin hydrochloride. WARNINGS Syncope and ‘‘First-dose’’ Effect: HYTRIN capsules, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. A similar effect can be This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 7 of 22 anticipated if therapy is interrupted for several days and then restarted. Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug. Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120-160 beats per minute. Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered. To decrease the likelihood of syncope or excessive hypotension, treatment should always be initiated with a 1 mg dose of terazosin, given at bedtime. The 2 mg, 5 mg and 10 mg capsules are not indicated as initial therapy. Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution. The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy. In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the ‘‘first-dose” effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given terazosin at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse effects all occurred within 90 minutes of dosing. In three placebo-controlled BPH studies 1, 2, and 3 (see CLINICAL PHARMACOLOGY), the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively. In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. There is evidence that the orthostatic effect of terazosin is greater, even in chronic use, shortly after dosing. The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. Priapism: Rarely, (probably less than once in every several thousand patients) terazosin and other α1-antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported. Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS: Information for Patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 8 of 22 PRECAUTIONS General: Prostatic Cancer Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Therefore, patients thought to have BPH should be examined prior to starting HYTRIN therapy to rule out the presence of carcinoma of the prostate. Intraoperative Floppy Iris Syndrome (IFIS) Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on/or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery. Orthostatic Hypotension While syncope is the most severe orthostatic effect of terazosin (see Warnings), other symptoms of lowered blood pressure, such as dizziness, lightheadedness and palpitations, were more common and occurred in some 28% of patients in clinical trials of hypertension. In BPH clinical trials, 21% of the patients experienced one or more of the following: dizziness, hypotension, postural hypotension, syncope, and vertigo. Patients with occupations in which such events represent potential problems should be treated with particular caution. Information for Patients (see Patient Package Insert): Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and to avoid driving or hazardous tasks for 12 hours after the first dose, after a dosage increase and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of terazosin therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with terazosin, requiring caution in people who must drive or operate heavy machinery. Patients should be advised about the possibility of priapism as a result of treatment with HYTRIN and other similar medications. Patients should know that this reaction to HYTRIN is extremely rare, but that if it is not brought to immediate medical attention, it can lead to permanent erectile dysfunction (impotence). Laboratory Tests: Small but statistically significant decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin were observed in controlled clinical trials. These laboratory findings suggested the possibility of hemodilution. Treatment with terazosin for up to 24 months had no significant effect on prostate specific antigen (PSA) levels. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 9 of 22 Drug Interactions: In controlled trials, terazosin has been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole); 3) anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride); 4) antigout (e.g., allopurinol); 5) antihistamines (e.g., chlorpheniramine); 6) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); 7) corticosteroids; 8) gastrointestinal agents (e.g., antacids); 9) hypoglycemics; 10) sedatives and tranquilizers (e.g., diazepam). Use with Other Drugs: In a study (n=24) where terazosin and verapamil were administered concomitantly, terazosin’s mean AUC0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in Cmax (25%) and Cmin (32%) means. Terazosin mean Tmax decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. In a study (n=6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril (see Dosage and Administration). Carcinogenesis, Mutagenesis, Impairment of Fertility: Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay). Terazosin, administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day (70, 350, and 2100 mg/M2/day), for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum recommended human dose of 20 mg (12 mg/M2). Female rats were unaffected. Terazosin was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day (110 mg/M2; 9 times the maximum recommended human dose). The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man. The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8, 30 and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg (240 mg/M2; 20 times the maximum recommended human dose) and five of 19 male rats given 120 mg/kg (960 mg/M2; 80 times the maximum recommended human dose) failed to sire a litter. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 10 of 22 Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy. Oral administration of terazosin for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day (29 and 175 times the maximum recommended human dose), but not in rats exposed to 8 mg/kg/day (> 6 times the maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day (> 500 times the maximum recommended human dose) for three months but not after one year when dosed with 20 mg/kg/day (38 times the maximum recommended human dose). This lesion has also been seen with Minipress®, another (marketed) selective-alpha-1 blocking agent. Pregnancy: Teratogenic effects: Pregnancy Category C. Terazosin was not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose. Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose. Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. These findings (in both species) were most likely secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established. HYTRIN is not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus. Nonteratogenic effects: In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period. Nursing Mothers: It is not known whether terazosin is excreted in breast milk. Because many drugs are excreted in breast milk, caution should be exercised when terazosin is administered to a nursing woman. Pediatric Use: Safety and effectiveness in children have not been determined. ADVERSE REACTIONS Benign Prostatic Hyperplasia The incidence of treatment-emergent adverse events has been ascertained from clinical trials conducted worldwide. All adverse events reported during these trials were recorded as adverse reactions. The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-a-day administration of terazosin at doses ranging from 1 to 20 mg. Table 1 summarizes those adverse events reported for patients in these trials when the incidence rate in the terazosin group was at least 1% and was greater than that for the placebo group, or where the reaction is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 11 of 22 patients receiving terazosin than in patients receiving placebo. The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events (see PRECAUTIONS) adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. TABLE 1 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED TRIALS BENIGN PROSTATIC HYPERPLASIA Body System Terazosin (N=636) Placebo (N=360) BODY AS A WHOLE †Asthenia 7.4%* 3.3% Flu Syndrome 2.4% 1.7% Headache 4.9% 5.8% CARDIOVASCULAR SYSTEM Hypotension 0.6% 0.6% Palpitations 0.9% 1.1% Postural Hypotension 3.9%* 0.8% Syncope 0.6% 0.0% DIGESTIVE SYSTEM Nausea 1.7% 1.1% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.9% 0.3% Weight Gain 0.5% 0.0% NERVOUS SYSTEM Dizziness 9.1%* 4.2% Somnolence 3.6%* 1.9% Vertigo 1.4% 0.3% RESPIRATORY SYSTEM Dyspnea 1.7% 0.8% Nasal Congestion/Rhinitis 1.9%* 0.0% SPECIAL SENSES Blurred Vision/Amblyopia 1.3% 0.6% UROGENITAL SYSTEM Impotence 1.6%* 0.6% Urinary Tract Infection 1.3% 3.9%* This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 12 of 22 † Includes weakness, tiredness, lassitude and fatigue. * p ≤ 0.05 comparison between groups. Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 2. TABLE 2 DISCONTINUATION DURING PLACEBO-CONTROLLED TRIALS BENIGN PROSTATIC HYPERPLASIA Body System Terazosin (N=636) Placebo (N=360) BODY AS A WHOLE Fever 0.5% 0.0% Headache 1.1% 0.8% CARDIOVASCULAR SYSTEM Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.0% DIGESTIVE SYSTEM Nausea 0.5% 0.3% NERVOUS SYSTEM Dizziness 2.0% 1.1% Vertigo 0.5% 0.0% RESPIRATORY SYSTEM Dyspnea 0.5% 0.3% SPECIAL SENSES Blurred Vision/Amblyopia 0.6% 0.0% UROGENITAL SYSTEM Urinary Tract Infection 0.5% 0.3% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 13 of 22 Hypertension The prevalence of adverse reactions has been ascertained from clinical trials conducted primarily in the United States. All adverse experiences (events) reported during these trials were recorded as adverse reactions. The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once-a-day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 to 40 mg. Table 3 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common in patients receiving terazosin than in patients receiving placebo. Similar adverse reaction rates were observed in placebo- controlled monotherapy trials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 14 of 22 TABLE 3 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED TRIALS HYPERTENSION Body System Terazosin (N=859) Placebo (N=506) BODY AS A WHOLE †Asthenia 11.3%* 4.3% Back Pain 2.4% 1.2% Headache 16.2% 15.8% CARDIOVASCULAR SYSTEM Palpitations 4.3%* 1.2% Postural Hypotension 1.3% 0.4% Tachycardia 1.9% 1.2% DIGESTIVE SYSTEM Nausea 4.4%* 1.4% METABOLIC AND NUTRITIONAL DISORDERS Edema 0.9% 0.6% Peripheral Edema 5.5%* 2.4% Weight Gain 0.5% 0.2% MUSCULOSKELETAL SYSTEM Pain-Extremities 3.5% 3.0% NERVOUS SYSTEM Depression 0.3% 0.2% Dizziness 19.3%* 7.5% Libido Decreased 0.6% 0.2% Nervousness 2.3% 1.8% Paresthesia 2.9% 1.4% Somnolence 5.4%* 2.6% RESPIRATORY SYSTEM Dyspnea 3.1% 2.4% Nasal Congestion 5.9%* 3.4% Sinusitis 2.6% 1.4% SPECIAL SENSES Blurred Vision 1.6%* 0.0% UROGENITAL SYSTEM Impotence 1.2% 1.4% † Includes weakness, tiredness, lassitude and fatigue. * Statistically significant at p=0.05 level. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 15 of 22 Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The following additional adverse reactions were reported by at least 1% of 1987 patients who received terazosin in controlled or open, short- or long-term clinical trials or have been reported during marketing experience: Body as a Whole: chest pain, facial edema, fever, abdominal pain, neck pain, shoulder pain; Cardiovascular System: arrhythmia, vasodilation; Digestive System: constipation, diarrhea, dry mouth, dyspepsia, flatulence, vomiting; Metabolic/Nutritional Disorders: gout; Musculoskeletal System: arthralgia, arthritis, joint disorder, myalgia; Nervous System: anxiety, insomnia; Respiratory System: bronchitis, cold symptoms, epistaxis, flu symptoms, increased cough, pharyngitis, rhinitis; Skin and Appendages: pruritus, rash, sweating; Special Senses: abnormal vision, conjunctivitis, tinnitus; Urogenital System: urinary frequency, urinary incontinence primarily reported in postmenopausal women, urinary tract infection. The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 4. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 16 of 22 TABLE 4 DISCONTINUATIONS DURING PLACEBO-CONTROLLED TRIALS HYPERTENSION Body System Terazosin (N=859) Placebo (N=506) BODY AS A WHOLE Asthenia 1.6% 0.0% Headache 1.3% 1.0% CARDIOVASCULAR SYSTEM Palpitations 1.4% 0.2% Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.2% Tachycardia 0.6% 0.0% DIGESTIVE SYSTEM Nausea 0.8% 0.0% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.6% 0.0% NERVOUS SYSTEM Dizziness 3.1% 0.4% Paresthesia 0.8% 0.2% Somnolence 0.6% 0.2% RESPIRATORY SYSTEM Dyspnea 0.9% 0.6% Nasal Congestion 0.6% 0.0% SPECIAL SENSES Blurred Vision 0.6% 0.0% Post-marketing Experience Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. There have been reports of priapism and thrombocytopenia during post-marketing surveillance. Atrial fibrillation has been reported. During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS) OVERDOSAGE Should overdosage of HYTRIN lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 17 of 22 vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that terazosin is 90-94% protein bound; therefore, dialysis may not be of benefit. DOSAGE AND ADMINISTRATION If HYTRIN administration is discontinued for several days, therapy should be reinstituted using the initial dosing regimen. Benign Prostatic Hyperplasia: Initial Dose: 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded as an initial dose. Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response. Subsequent Doses: The dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. Doses of 10 mg once daily are generally required for the clinical response. Therefore, treatment with 10 mg for a minimum of 4–6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. Although some additional patients responded at a 20 mg daily dose, there was an insufficient number of patients studied to draw definitive conclusions about this dose. There are insufficient data to support the use of higher doses for those patients who show inadequate or no response to 20 mg daily. If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. Use with Other Drugs: Caution should be observed when HYTRIN is administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. When using HYTRIN and other antihypertensive agents concomitantly, dosage reduction and retitration of either agent may be necessary (see Precautions). Hypotension has been reported when Hytrin has been used with phosphodiesterase-5 (PDE-5) inhibitors Hypertension: The dose of HYTRIN and the dose interval (12 or 24 hours) should be adjusted according to the patient’s individual blood pressure response. The following is a guide to its administration: Initial Dose: 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded. This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects. Subsequent Doses: The dose may be slowly increased to achieve the desired blood pressure response. The usual recommended dose range is 1 mg to 5 mg administered once a day; however, some patients may benefit from doses as high as 20 mg per day. Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 18 of 22 studied. Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. It may also be helpful to measure blood pressure 2-3 hours after dosing to see if the maximum and minimum responses are similar, and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response. If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. If terazosin administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. In clinical trials, except for the initial dose, the dose was given in the morning. Use With Other Drugs: (see above) HOW SUPPLIED HYTRIN capsules (terazosin hydrochloride capsules) are available in four dosage strengths: 1 mg grey capsules (imprinted with and the Abbo-Code HH): Bottles of 100 .............................................................(NDC 0074-3805-13), Abbo-Pac® unit dose strip packages of 100 capsules ...........................................................(NDC 0074-3805-11). 2 mg yellow capsules (imprinted with and the Abbo-Code HY): Bottles of 100 .............................................................(NDC 0074-3806-13), Abbo-Pac® unit dose strip packages of 100 capsules ...........................................................(NDC 0074-3806-11). 5 mg red capsules (imprinted with and the Abbo-Code HK): Bottles of 100 .............................................................(NDC 0074-3807-13), Abbo-Pac® unit dose strip packages of 100 capsules ...........................................................(NDC 0074-3807-11). 10 mg blue capsules (imprinted with and the Abbo-Code HN): Bottles of 100 .............................................................(NDC 0074-3808-13), Abbo-Pac® unit dose strip packages of 100 capsules ...........................................................(NDC 0074-3808-11). Recommended storage: Store at controlled room temperature between 20-25°C (68- 77°F). See USP. Protect from light and moisture. Revised: February, 2001 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 19 of 22 (Nos. 3805, 3806, 3807, 3808) 03-4995-R2-Rev. Oct., 1999 PATIENT INFORMATION ABOUT HYTRIN® (HI-TRIN) Generic Name: terazosin (ter-A-zo-sin) hydrochloride When used to treat HYPERTENSION or BENIGN PROSTATIC HYPERPLASIA (BPH) Please read this leaflet before you start taking HYTRIN. Also, read it each time you get a new prescription. This is a summary and should NOT take the place of a full discussion with your doctor who has additional information about HYTRIN. You and your doctor should discuss HYTRIN and your condition before you start taking it and at your regular check-ups. HYTRIN is used to treat high blood pressure (hypertension). HYTRIN is also used to treat benign prostatic hyperplasia (BPH) in men. This leaflet describes HYTRIN as a treatment for hypertension or BPH. What is hypertension (high blood pressure)? Blood pressure is the tension of the blood within the blood vessels. If blood is pumped too forcefully, or if the blood vessels are too narrow, the pressure of the blood against the walls of the vessels rises. If high blood pressure is not treated, over time, the increased pressure can damage blood vessels or it can cause the heart to work too hard and may decrease the flow of blood to the heart, brain, and kidneys. As a result, these organs may become damaged and not function correctly. If high blood pressure is controlled, this damage is less likely to happen. Treatment options for hypertension Non-drug treatments are sometimes effective in controlling mild hypertension. The most important lifestyle changes to lower blood pressure are to lose weight, reduce salt, fat, and alcohol in the diet, quit smoking, and exercise regularly. However, many hypertensive patients require one or more ongoing medications to control their blood pressure. There are different kinds of medications used to treat hypertension. Your doctor has prescribed HYTRIN for you. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 20 of 22 What HYTRIN does to treat hypertension HYTRIN works by relaxing blood vessels so that blood passes through them more easily. This helps to lower blood pressure. What is BPH? The prostate is a gland located below the bladder of men. It surrounds the urethra (you-REETH-rah), which is a tube that drains urine from the bladder. BPH is an enlargement of the prostate gland. The symptoms of BPH, however, can be caused by an increase in the tightness of muscles in the prostate. If the muscles inside the prostate tighten, they can squeeze the urethra and slow the flow of urine. This can lead to symptoms such as: • a weak or interrupted stream when urinating • a feeling that you cannot empty your bladder completely • a feeling of delay when you start to urinate • a need to urinate often, especially at night, or • a feeling that you must urinate right away. Treatment options for BPH There are three main treatment options for BPH: • Program of monitoring or "Watchful Waiting". Some men have an enlarged prostate gland, but no symptoms, or symptoms that are not bothersome. If this applies, you and your doctor may decide on a program of monitoring including regular checkups, instead of medication or surgery. • Medication. There are different kinds of medication used to treat BPH. Your doctor has prescribed HYTRIN for you. See "What HYTRIN does to treat BPH" below. • Surgery. Some patients may need surgery. Your doctor can describe several different surgical procedures to treat BPH. Which procedure is best depends on your symptoms and medical condition. What HYTRIN does to treat BPH HYTRIN relaxes the tightness of a certain type of muscle in the prostate and at the opening of the bladder. This may increase the rate of urine flow and/or decrease the symptoms you are having. • HYTRIN helps relieve the symptoms of BPH. It does NOT change the size of the prostate, which may continue to grow. However, a larger prostate does not necessarily cause more or worse symptoms. • If HYTRIN is helping you, you should notice an effect on your particular symptoms in 2 to 4 weeks of starting to take the medication. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 21 of 22 • Even though you take HYTRIN and it may help you, HYTRIN may not prevent the need for surgery in the future. Other important facts about HYTRIN for BPH • You should see an effect on your symptoms in 2 to 4 weeks. So, you will need to continue seeing your doctor to check your progress regarding your BPH and to monitor your blood pressure in addition to your other regular check-ups. • Your doctor has prescribed HYTRIN for your BPH and not for prostate cancer. However, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These checks should continue even if you are taking HYTRIN. HYTRIN is not a treatment for prostate cancer. • About Prostate Specific Antigen (PSA). Your doctor may have done a blood test called PSA. Your doctor is aware that HYTRIN does not affect PSA levels. You may want to ask your doctor more about this if you have had a PSA test done. What you should know while taking HYTRIN for hypertension or BPH WARNINGS HYTRIN Can Cause A Sudden Drop in Blood Pressure After the VERY FIRST DOSE. You may feel dizzy, faint, or "light-headed" particularly after you get up from bed or from a chair. This is more likely to occur after you've taken the first few doses, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then re-start treatment. Because of this effect, your doctor may have told you to take HYTRIN at bedtime. If you take HYTRIN at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medicine affects you. It is also important to get up slowly from a chair or bed at any time until you learn how you react to HYTRIN. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. • You will start with a 1 mg dose of HYTRIN. Then the dose will be increased as your body gets used to the effect of the medication. • Other side effects you could have while taking HYTRIN include drowsiness, blurred or hazy vision, nausea, or "puffiness" of the feet or hands. Discuss any unexpected effects you notice with your doctor. Extremely rarely, HYTRIN and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DN1075V1 CR 25-003537 August 22, 2005 Page 22 of 22 How to take HYTRIN Follow your doctor's instructions about how to take HYTRIN. You must take it every day at the dose prescribed. Talk with your doctor if you don't take it for a few days, you may have to restart it at a 1 mg dose and be cautious about possible dizziness. Do not share HYTRIN with anyone else; it was prescribed only for you. Keep HYTRIN and all medicines out of the reach of children. Store capsules between 68 - 77°F (20 -25°C) Protect from light and moisture. FOR MORE INFORMATION ABOUT HYTRIN AND HYPERTENSION OR BPH, TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER. Revised Oct., 1999 ( This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:14.908825	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/19057Orig1s021, 20347Orig1s009 lbl.pdf', 'application_number': 19057, 'submission_type': 'SUPPL ', 'submission_number': 21}
11,431	---------- HYTRIN - terazosin hydrochloride tablet Abbott Laboratories HYTRIN® (terazosin hydrochloride) Description HYTRIN (terazosin hydrochloride), an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following chemical name and structural formula: (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-, monohydrochloride, dihydrate. Structural Formula Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has a molecular weight of 459.93. HYTRIN tablets (terazosin hydrochloride tablets) for oral ingestion are supplied in four dosage strengths containing terazosin hydrochloride equivalent to 1 mg, 2 mg, 5 mg, or 10 mg of terazosin. Inactive Ingredients 1 mg tablet: corn starch, lactose, magnesium stearate, povidone and talc. 2 mg tablet: corn starch, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. 5 mg tablet: corn starch, iron oxide, lactose, magnesium stearate, povidone and talc. 10 mg tablet: corn starch, D&C Yellow No. 10, FD&C Blue No. 2, lactose, magnesium stearate, povidone and talc. CLINICAL PHARMACOLOGY Pharmacodynamics A. Benign Prostatic Hyperplasia (BPH) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: a static component and a dynamic component. The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity of BPH symptoms or the degree of urinary obstruction.1 The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-l adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-l adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-l adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. Terazosin has been extensively studied in 1222 men with symptomatic BPH. In three placebo- controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were systematically quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0-3, for a total score of 27 points. Results from these studies indicated that terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows: Symptom Score Peak Flow Rate (Range 0-27) (mL/sec) N Mean Mean (%) N Mean Mean (%) Baseline Change Baseline Change Study 1 (10 mg)a Titration to fixed dose (12 wks) Placebo 55 9.7 -2.3 (24) 54 10.1 +1.0 (10) Terazosin 54 10.1 -4.5 (45)52 8.8 +3.0 (34) Study 2 (2, 5, 10, 20 mg) b Titration to response This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (24 wks) Placebo 89 12.5 -3.8 (30) 88 8.8 +1.4 (16) Terazosin 85 12.2 -5.3 (43)* 84 8.4 +2.9 (35)* Study 3 (1, 2, 5, 10 mg) c Titration to response (24 wks) Placebo 74 10.4 -1.1 (11) 74 8.8 +1.2 (14) Terazosin 73 10.9 -4.6 (42)73 8.6 +2.6 (30) a Highest dose 10 mg shown. b 23% of patients on 10 mg, 41% of patients on 20 mg. c 67% of patients on 10 mg. * Significantly (p ≤ 0.05) more improvement than placebo. In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with HYTRIN from week 2 (or the first clinic visit) and throughout the study duration. Analysis of the effect of HYTRIN on individual urinary symptoms demonstrated that compared to placebo, HYTRIN significantly improved the symptoms of hesitancy, intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia. Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. In studies 1 and 3, patients treated with HYTRIN had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. In a short term study (Study 1), patients were randomized to either 2, 5 or 10 mg of HYTRIN or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo (Figure 1). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 1. Study 1 Mean Change in Total Symptom Score Mean Increase in Peak Flow Rate (mL/sec) from Baseline+ from Baseline+ Graph + for baseline values see above table * p ≤ 0.05, compared to placebo group In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of HYTRIN on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3): Figure 2. Mean Change in Total Symptom Score from Baseline Long-term, Open-label, Non-placebo Controlled Study (N = 494) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Graph * p ≤ 0.05 vs. baseline mean baseline = 10.7 Figure 3. Mean Change in Peak Flow Rate from Baseline Long-term, Open-label, Non-placebo Controlled Study (N = 494) Graph * p ≤ 0.05 vs. baseline mean baseline = 9.9 In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mean Changes in Blood Pressure from Baseline to Final Visit in all Double-blind, Placebo-controlled Studies SBP Group Placebo Normotensive Patients DBP ≤ 90 mm Hg N Mean Change 293 -0.1 Hypertensive Patients DBP > 90 mm Hg N Mean Change 45 -5.8 (mm Hg) DBP Terazosin Placebo 519 293 -3.3* +0.4 65 45 -14.4* -7.1 (mm Hg) Terazosin 519 -2.2* 65 -15.1* * p ≤ 0.05 vs. placebo B. Hypertension In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1 adrenoceptors. Terazosin decreases blood pressure gradually within 15 minutes following oral administration. Patients in clinical trials of terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5-20 mg/day, and had mild (about 77%, diastolic pressure 95-105 mmHg) or moderate (23%, diastolic pressure 105-115 mmHg) hypertension. Because terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). Blood pressure responses were measured at the end of the dosing interval (usually 24 hours) and effects were shown to persist throughout the interval, with the usual supine responses 5-10 mmHg systolic and 3.5-8 mmHg diastolic greater than placebo. The responses in the standing position tended to be somewhat larger, by 1-3 mmHg, although this was not true in all studies. The magnitude of the blood pressure responses was similar to prazosin and less than hydrochlorothiazide (in a single study of hypertensive patients). In measurements 24 hours after dosing, heart rate was unchanged. Limited measurements of peak response (2-3 hours after dosing) during chronic terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5-20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-related side effects, such as dizziness, palpitations, or orthostatic complaints, are seen within a few hours after dosing. The greater blood pressure effect associated with peak plasma concentrations (first few hours after dosing) appears somewhat more position-dependent (greater in the erect position) than the effect of terazosin at 24 hours and in the erect position there is also a 6-10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg, compared to 4% of a placebo group. There was a tendency for patients to gain weight during terazosin therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin gained a mean of 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2 pounds respectively in the placebo group. Both differences were statistically significant. During controlled clinical trials, patients receiving terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low- density and very-low-density lipoprotein fractions. No significant changes were observed in high- density lipoprotein fraction and triglycerides compared to placebo. Analysis of clinical laboratory data following administration of terazosin suggested the possibility of hemodilution based on decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin. Decreases in hematocrit and total protein have been observed with alpha-blockade and are attributed to hemodilution. Pharmacokinetics This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Relative to solution, terazosin hydrochloride administered as HYTRIN tablets is essentially completely absorbed in man. Food had little or no effect on the extent of absorption but food delayed the time to peak concentration by about 1 hour. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14.0 and 11.4 hours for the age group ≥ 70 years and the age group of 20-39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20-39 years of age. The drug is highly bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man. INDICATIONS AND USAGE HYTRIN (terazosin hydrochloride) is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH). There is a rapid response, with approximately 70% of patients experiencing an increase in urinary flow and improvement in symptoms of BPH when treated with HYTRIN. The long- term effects of HYTRIN on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined. HYTRIN tablets are also indicated for the treatment of hypertension. HYTRIN tablets can be used alone or in combination with other antihypertensive agents such as diuretics or beta-adrenergic blocking agents. CONTRAINDICATIONS HYTRIN tablets are contraindicated in patients known to be hypersensitive to terazosin hydrochloride. WARNINGS Syncope and ‘‘First-dose’’ Effect This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HYTRIN tablets, like other alpha-adrenergic blocking agents, can cause marked lowering of blood pressure, especially postural hypotension, and syncope in association with the first dose or first few days of therapy. A similar effect can be anticipated if therapy is interrupted for several days and then restarted. Syncope has also been reported with other alpha-adrenergic blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug. Syncope is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120-160 beats per minute. Additionally, the possibility of the contribution of hemodilution to the symptoms of postural hypotension should be considered. To decrease the likelihood of syncope or excessive hypotension, treatment should always be initiated with a 1 mg dose of HYTRIN tablets, given at bedtime. The 2 mg, 5 mg and 10 mg tablets are not indicated as initial therapy. Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution. The patient should be cautioned to avoid situations, such as driving or hazardous tasks, where injury could result should syncope occur during initiation of therapy. In early investigational studies, where increasing single doses up to 7.5 mg were given at 3 day intervals, tolerance to the first dose phenomenon did not necessarily develop and the ‘‘first-dose” effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given HYTRIN tablets at doses of 2.5, 5 and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) was seen in two others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse effects all occurred within 90 minutes of dosing. In three placebo-controlled BPH studies 1, 2, and 3 (see CLINICAL PHARMACOLOGY), the incidence of postural hypotension in the terazosin treated patients was 5.1%, 5.2%, and 3.7% respectively. In multiple dose clinical trials involving nearly 2000 hypertensive patients treated with HYTRIN tablets, syncope was reported in about 1% of patients. Syncope was not necessarily associated only with the first dose. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary. There is evidence that the orthostatic effect of HYTRIN tablets is greater, even in chronic use, shortly after dosing. The risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Priapism Rarely, (probably less than once in every several thousand patients), terazosin and other α1 antagonists have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported. Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS - Information for Patients). PRECAUTIONS General Prostatic Cancer Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Therefore, patients thought to have BPH should be examined prior to starting HYTRIN therapy to rule out the presence of carcinoma of the prostate. Intraoperative Floppy Iris Syndrome (IFIS) Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on/or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery. Orthostatic Hypotension While syncope is the most severe orthostatic effect of HYTRIN tablets (see WARNINGS), other symptoms of lowered blood pressure, such as dizziness, lightheadedness and palpitations, were more common and occurred in some 28% of patients in clinical trials of hypertension. In BPH clinical trials, 21% of the patients experienced one or more of the following: dizziness, hypotension, postural hypotension, syncope, and vertigo. Patients with occupations in which such events represent potential problems should be treated with particular caution. Information for Patients (see Patient Package Insert) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and to avoid driving or hazardous tasks for 12 hours after the first dose, after a dosage increase and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of HYTRIN therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with HYTRIN tablets, requiring caution in people who must drive or operate heavy machinery. Patients should be advised about the possibility of priapism as a result of treatment with HYTRIN and other similar medications. Patients should know that this reaction to HYTRIN is extremely rare, but that if it is not brought to immediate medical attention, it can lead to permanent erectile dysfunction (impotence). Laboratory Tests Small but statistically significant decreases in hematocrit, hemoglobin, white blood cells, total protein and albumin were observed in controlled clinical trials. These laboratory findings suggested the possibility of hemodilution. Treatment with HYTRIN for up to 24 months had no significant effect on prostate specific antigen (PSA) levels. Drug Interactions Concomitant administration of HYTRIN with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION). In controlled trials, HYTRIN tablets have been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. HYTRIN tablets have also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. HYTRIN tablets have been used concomitantly in at least 50 patients on the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole); 3) anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride); 4) antigout (e.g., allopurinol); 5) antihistamines (e.g., This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda chlorpheniramine); 6) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); 7) corticosteroids; 8) gastrointestinal agents (e.g., antacids); 9) hypoglycemics; 10) sedatives and tranquilizers (e.g., diazepam). Use with Other Drugs In a study (n=24) where terazosin and verapamil were administered concomitantly, terazosin’s mean AUC0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in Cmax (25%) and Cmin (32%) means. Terazosin mean Tmax decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. In a study (n=6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril (see DOSAGE AND ADMINISTRATION). Carcinogenesis, Mutagenesis, Impairment of Fertility HYTRIN was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay). HYTRIN, administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day (70, 350, and 2100 mg/M2/day), for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum recommended human dose of 20 mg (12 mg/M2). Female rats were unaffected. HYTRIN was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day (110 mg/M2; 9 times the maximum recommended human dose). The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man. The effect of HYTRIN on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8, 30 and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg (240 mg/M2; 20 times the maximum recommended human dose), and five of 19 male rats given 120 mg/kg (960 mg/M2; 80 times the maximum recommended human dose), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy. Oral administration of HYTRIN for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day (29 and 175 times the maximum recommended human dose), but not in rats exposed to 8 mg/kg/day (> 6 times the maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day (> 500 times the maximum recommended human dose) for three months but not after one year when dosed with 20 mg/kg/day (38 times the maximum recommended human dose). This lesion has also been seen with Minipress®, another (marketed) selective-alpha-1 blocking agent. Pregnancy Teratogenic Effects Pregnancy Category C HYTRIN was not teratogenic in either rats or rabbits when administered at oral doses up to 280 and 60 times, respectively, the maximum recommended human dose. Fetal resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum recommended human dose. Increased fetal resorptions, decreased fetal weight and an increased number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the maximum recommended human dose. These findings (in both species) were most likely secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established. HYTRIN is not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus. Nonteratogenic Effects In a peri- and post-natal development study in rats, significantly more pups died in the group dosed with 120 mg/kg/day (> 75 times the maximum recommended human dose) than in the control group during the three-week postpartum period. Nursing Mothers It is not known whether terazosin is excreted in breast milk. Because many drugs are excreted in breast milk, caution should be exercised when HYTRIN tablets are administered to a nursing woman. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Safety and effectiveness in children have not been determined. ADVERSE REACTIONS Benign Prostatic Hyperplasia The incidence of treatment-emergent adverse events has been ascertained from clinical trials conducted worldwide. All adverse events reported during these trials were recorded as adverse reactions. The incidence rates presented below are based on combined data from six placebo- controlled trials involving once-a-day administration of terazosin at doses ranging from 1 to 20 mg. Table 1 summarizes those adverse events reported for patients in these trials when the incidence rate in the terazosin group was at least 1% and was greater than that for the placebo group, or where the reaction is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in patients receiving terazosin than in patients receiving placebo. The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events (see PRECAUTIONS) adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals. Table 1. Adverse Reactions During Placebo-controlled Trials Benign Prostatic Hyperplasia Body System Terazosin Placebo (N = 636) (N = 360) BODY AS A WHOLE †Asthenia 7.4%* 3.3% Flu Syndrome 2.4% 1.7% Headache 4.9% 5.8% CARDIOVASCULAR SYSTEM Hypotension 0.6% 0.6% Palpitations 0.9% 1.1% Postural Hypotension 3.9%* 0.8% Syncope 0.6% 0.0% DIGESTIVE SYSTEM Nausea 1.7% 1.1% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.9% 0.3% Weight Gain 0.5% 0.0% NERVOUS SYSTEM Dizziness 9.1%* 4.2% Somnolence 3.6%* 1.9% Vertigo 1.4% 0.3% RESPIRATORY SYSTEM Dyspnea 1.7% 0.8% Nasal Congestion/Rhinitis 1.9%* 0.0% SPECIAL SENSES Blurred Vision/Amblyopia 1.3% 0.6% UROGENITAL SYSTEM Impotence 1.6%* 0.6% Urinary Tract Infection 1.3% 3.9%* † Includes weakness, tiredness, lassitude and fatigue. * p ≤ 0.05 comparison between groups. Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies. The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 2. Table 2. Discontinuation During Placebo-controlled Trials Benign Prostatic Hyperplasia This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Body System Terazosin Placebo (N = 636) (N = 360) BODY AS A WHOLE Fever 0.5% 0.0% Headache 1.1% 0.8% CARDIOVASCULAR SYSTEM Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.0% DIGESTIVE SYSTEM Nausea 0.5% 0.3% NERVOUS SYSTEM Dizziness 2.0% 1.1% Vertigo 0.5% 0.0% RESPIRATORY SYSTEM Dyspnea 0.5% 0.3% SPECIAL SENSES Blurred Vision/Amblyopia 0.6% 0.0% UROGENITAL SYSTEM Urinary Tract Infection 0.5% 0.3% Hypertension The prevalence of adverse reactions has been ascertained from clinical trials conducted primarily in the United States. All adverse experiences (events) reported during these trials were recorded as adverse reactions. The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once-a-day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 to 40 mg. Table 3 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in patients receiving terazosin than in patients receiving placebo. Similar adverse reaction rates were observed in placebo-controlled monotherapy trials. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3. Adverse Reactions During Placebo-controlled Trials Hypertension Body System Terazosin Placebo (N = 859) (N = 506) BODY AS A WHOLE †Asthenia 11.3%* 4.3% Back Pain 2.4% 1.2% Headache 16.2% 15.8% CARDIOVASCULAR SYSTEM Palpitations 4.3%* 1.2% Postural Hypotension 1.3% 0.4% Tachycardia 1.9% 1.2% DIGESTIVE SYSTEM Nausea 4.4%* 1.4% METABOLIC AND NUTRITIONAL DISORDERS Edema 0.9% 0.6% Peripheral Edema 5.5%* 2.4% Weight Gain 0.5% 0.2% MUSCULOSKELETAL SYSTEM Pain-Extremities 3.5% 3.0% NERVOUS SYSTEM Depression 0.3% 0.2% Dizziness 19.3%* 7.5% Libido Decreased 0.6% 0.2% Nervousness 2.3% 1.8% Paresthesia 2.9% 1.4% Somnolence 5.4%* 2.6% RESPIRATORY SYSTEM Dyspnea 3.1% 2.4% Nasal Congestion 5.9%* 3.4% Sinusitis 2.6% 1.4% SPECIAL SENSES This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Blurred Vision 1.6%* 0.0% UROGENITAL SYSTEM Impotence 1.2% 1.4% † Includes weakness, tiredness, lassitude and fatigue. * Statistically significant at p = 0.05 level. Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The following additional adverse reactions were reported by at least 1% of 1987 patients who received terazosin in controlled or open, short- or long-term clinical trials or have been reported during marketing experience: Body as a Whole chest pain, facial edema, fever, abdominal pain, neck pain, shoulder pain Cardiovascular System arrhythmia, vasodilation Digestive System constipation, diarrhea, dry mouth, dyspepsia, flatulence, vomiting Metabolic/Nutritional Disorders gout Musculoskeletal System arthralgia, arthritis, joint disorder, myalgia Nervous System anxiety, insomnia Respiratory System bronchitis, cold symptoms, epistaxis, flu symptoms, increased cough, pharyngitis, rhinitis Skin and Appendages pruritus, rash, sweating This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Senses abnormal vision, conjunctivitis, tinnitus Urogenital System urinary frequency, urinary incontinence primarily reported in postmenopausal women, urinary tract infection. The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment. The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the terazosin group and being reported more often than in the placebo group, are shown in Table 4. Table 4. Discontinuations During Placebo-controlled Trials Hypertension Body System Terazosin Placebo (N = 859) (N = 506) BODY AS A WHOLE Asthenia 1.6% 0.0% Headache 1.3% 1.0% CARDIOVASCULAR SYSTEM Palpitations 1.4% 0.2% Postural Hypotension 0.5% 0.0% Syncope 0.5% 0.2% Tachycardia 0.6% 0.0% DIGESTIVE SYSTEM Nausea 0.8% 0.0% METABOLIC AND NUTRITIONAL DISORDERS Peripheral Edema 0.6% 0.0% NERVOUS SYSTEM Dizziness 3.1% 0.4% Paresthesia 0.8% 0.2% Somnolence 0.6% 0.2% RESPIRATORY SYSTEM Dyspnea 0.9% 0.6% Nasal Congestion 0.6% 0.0% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPECIAL SENSES Blurred Vision 0.6% 0.0% Post-marketing Experience Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. There have been reports of priapism and thrombocytopenia during post-marketing surveillance. Atrial fibrillation has been reported. During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS). OVERDOSAGE Should overdosage of HYTRIN lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that HYTRIN is highly protein bound; therefore, dialysis may not be of benefit. DOSAGE AND ADMINISTRATION If HYTRIN administration is discontinued for several days, therapy should be reinstituted using the initial dosing regimen. Benign Prostatic Hyperplasia Initial Dose 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded as an initial dose. Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response. Subsequent Doses The dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. Doses of 10 mg once daily are generally This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda required for the clinical response. Therefore, treatment with 10 mg for a minimum of 4–6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. Although some additional patients responded at a 20 mg daily dose, there was an insufficient number of patients studied to draw definitive conclusions about this dose. There are insufficient data to support the use of higher doses for those patients who show inadequate or no response to 20 mg daily. Use with Other Drugs Caution should be observed when HYTRIN tablets are administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. When using HYTRIN tablets and other antihypertensive agents concomitantly, dosage reduction and retitration of either agent may be necessary (see PRECAUTIONS). Concomitant administration of HYTRIN with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking HYTRIN. Hypertension The dose of HYTRIN and the dose interval (12 or 24 hours) should be adjusted according to the patient's individual blood pressure response. The following is a guide to its administration: Initial Dose 1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded. This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects. Subsequent Doses The dose may be slowly increased to achieve the desired blood pressure response. The usual recommended dose range is 1 mg to 5 mg administered once a day; however, some patients may benefit from doses as high as 20 mg per day. Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied. Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. It may also be helpful to measure blood pressure 2-3 hours after dosing to see if the maximum and minimum responses are similar, and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response. If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. If terazosin administration is This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. In clinical trials, except for the initial dose, the dose was given in the morning. Use With Other Drugs (see above) HOW SUPPLIED HYTRIN tablets (terazosin hydrochloride tablets) are available in four dosage strengths: 1 mg, white tablets (bears the Abbott “A” logo and the Abbo-Code DF): Bottles of 100 (NDC 0074-3322-13). 2 mg, orange tablets (bears the Abbott “A” logo and the Abbo-Code DH): Bottles of 100 (NDC 0074-3323-13). 5 mg, tan tablets (bears the Abbott “A” logo and the Abbo-Code DJ): Bottles of 100 (NDC 0074-3324-13). 10 mg, green tablets (bears the Abbott “A” logo and the Abbo-Code DI): Bottles of 100 (NDC 0074-3325-13). Recommended storage Store below 86°F (30°C). REFERENCE 1. Lepor H. Role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. Prostate 1990; 3:75-84. Abbott Laboratories North Chicago, IL 60064, U.S.A. PATIENT INFORMATION ABOUT HYTRIN® (HI-TRIN) Generic Name: terazosin (ter-A-zo-sin) hydrochloride When used to treat HYPERTENSION or BENIGN PROSTATIC HYPERPLASIA (BPH) Please read this leaflet before you start taking HYTRIN. Also, read it each time you get a new prescription. This is a summary and should NOT take the place of a full discussion with your doctor This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda who has additional information about HYTRIN. You and your doctor should discuss HYTRIN and your condition before you start taking it and at your regular check-ups. HYTRIN is used to treat high blood pressure (hypertension). HYTRIN is also used to treat benign prostatic hyperplasia (BPH) in men. This leaflet describes HYTRIN as a treatment for hypertension or BPH. What Is Hypertension (High Blood Pressure)? Blood pressure is the tension of the blood within the blood vessels. If blood is pumped too forcefully, or if the blood vessels are too narrow, the pressure of the blood against the walls of the vessels rises. If high blood pressure is not treated, over time, the increased pressure can damage blood vessels or it can cause the heart to work too hard and may decrease the flow of blood to the heart, brain, and kidneys. As a result, these organs may become damaged and not function correctly. If high blood pressure is controlled, this damage is less likely to happen. Treatment Options for Hypertension Non-drug treatments are sometimes effective in controlling mild hypertension. The most important lifestyle changes to lower blood pressure are to lose weight, reduce salt, fat, and alcohol in the diet, quit smoking, and exercise regularly. However, many hypertensive patients require one or more ongoing medications to control their blood pressure. There are different kinds of medications used to treat hypertension. Your doctor has prescribed HYTRIN for you. What HYTRIN Does to Treat Hypertension HYTRIN works by relaxing blood vessels so that blood passes through them more easily. This helps to lower blood pressure. What is BPH? The prostate is a gland located below the bladder of men. It surrounds the urethra (you-REETH-rah), which is a tube that drains urine from the bladder. BPH is an enlargement of the prostate gland. The symptoms of BPH, however, can be caused by an increase in the tightness of muscles in the prostate. If the muscles inside the prostate tighten, they can squeeze the urethra and slow the flow of urine. This can lead to symptoms such as: • a weak or interrupted stream when urinating • a feeling that you cannot empty your bladder completely • a feeling of delay when you start to urinate This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • a need to urinate often, especially at night, or • a feeling that you must urinate right away. Treatment Options for BPH There are three main treatment options for BPH: • Program of monitoring or "Watchful Waiting". Some men have an enlarged prostate gland, but no symptoms, or symptoms that are not bothersome. If this applies, you and your doctor may decide on a program of monitoring including regular checkups, instead of medication or surgery. • Medication. There are different kinds of medication used to treat BPH. Your doctor has prescribed HYTRIN for you. See "What HYTRIN does to treat BPH" below. • Surgery. Some patients may need surgery. Your doctor can describe several different surgical procedures to treat BPH. Which procedure is best depends on your symptoms and medical condition. What HYTRIN Does to Treat BPH HYTRIN relaxes the tightness of a certain type of muscle in the prostate and at the opening of the bladder. This may increase the rate of urine flow and/or decrease the symptoms you are having. • HYTRIN helps relieve the symptoms of BPH. It does NOT change the size of the prostate, which may continue to grow. However, a larger prostate does not necessarily cause more or worse symptoms. • If HYTRIN is helping you, you should notice an effect on your particular symptoms in 2 to 4 weeks of starting to take the medication. • Even though you take HYTRIN and it may help you, HYTRIN may not prevent the need for surgery in the future. Other Important Facts About HYTRIN for BPH • You should see an effect on your symptoms in 2 to 4 weeks. So, you will need to continue seeing your doctor to check your progress regarding your BPH and to monitor your blood pressure in addition to your other regular check-ups. • Your doctor has prescribed HYTRIN for your BPH and not for prostate cancer. However, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda has had prostate cancer). These checks should continue even if you are taking HYTRIN. HYTRIN is not a treatment for prostate cancer. • About Prostate Specific Antigen (PSA). Your doctor may have done a blood test called PSA. Your doctor is aware that HYTRIN does not affect PSA levels. You may want to ask your doctor more about this if you have had a PSA test done. What You Should Know While Taking HYTRIN for Hypertension or BPH WARNINGS HYTRIN Can Cause A Sudden Drop in Blood Pressure After the VERY FIRST DOSE. You may feel dizzy, faint, or "light-headed" particularly after you get up from bed or from a chair. This is more likely to occur after you've taken the first few doses, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then re-start treatment. Because of this effect, your doctor may have told you to take HYTRIN at bedtime. If you take HYTRIN at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medicine affects you. It is also important to get up slowly from a chair or bed at any time until you learn how you react to HYTRIN. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better. • You will start with a 1 mg dose of HYTRIN. Then the dose will be increased as your body gets used to the effect of the medication. • Other side effects you could have while taking HYTRIN include drowsiness, blurred or hazy vision, nausea, or "puffiness" of the feet or hands. Discuss any unexpected effects you notice with your doctor. Extremely rarely, HYTRIN and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible. How to take HYTRIN Follow your doctor's instructions about how to take HYTRIN. You must take it every day at the dose prescribed. Talk with your doctor if you don't take it for a few days, you may have to restart it at a 1 mg dose and be cautious about possible dizziness. Do not share HYTRIN with anyone else; it was prescribed only for you. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Keep HYTRIN and all medicines out of the reach of children. Store tablets below 86°F (30°C) FOR MORE INFORMATION ABOUT HYTRIN AND HYPERTENSION OR BPH, TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER. Abbott Laboratories North Chicago, IL 60064, U.S.A. Printed in U.S.A. Revised: 07/2009 Abbott Laboratories This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:14.917842	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019057s022lbl.pdf', 'application_number': 19057, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,432	_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Urocit®-K safely and effectively. See full prescribing information for Urocit®-K. Urocit®-K (Potassium Citrate) Extended-release tablets for oral use Initial U.S. Approval: 1985 ----------------------------RECENT MAJOR CHANGES----------------------- Dosage and Administration, Urocit®-K 15 mEq (2.2, 2.3) 12/2009 Dosage Forms and Strengths, Urocit®-K 15 mEq (3) 12/2009 Description, Urocit®-K 15 mEq (11) 12/2009 Clinical Studies (14) 12/2009 How Supplied/Storage and Handling, Urocit®-K 15 mEq (16) 12/2009 ----------------------------INDICATIONS AND USAGE--------------------------- Urocit®-K is a citrate salt of potassium indicated for the management of: • Renal tubular acidosis (RTA) with calcium stones (1.1) • Hypocitraturic calcium oxalate nephrolithiasis of any etiology (1.2) • Uric acid lithiasis with or without calcium stones (1.3) ----------------------DOSAGE AND ADMINISTRATION----------------------- Objective: To restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6.0 to 7.0. • Severe hypocitraturia (urinary citrate < 150 mg/day): therapy should be initiated at 60 mEq per day; a dose of 30 mEq two times per day or 20 mEq three times per day with meals or within 30 minutes after meals or bedtime snack (2.2) • Mild to moderate hypocitraturia (urinary citrate >150 mg/day): therapy should be initiated at 30 mEq per day; a dose of 15 mEq two times per day or 10 mEq three times per day with meals or within 30 minutes after meals or bedtime snack (2.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Tablets: 5 mEq, 10 mEq and 15 mEq (3) -------------------------------CONTRAINDICATIONS------------------------------ • Patients with hyperkalemia (or who have conditions predisposing them to hyperkalemia). Such conditions include chronic renal failure, uncontrolled diabetes mellitus, acute dehydration, strenuous physical exercise in unconditioned individuals, adrenal insufficiency, extensive tissue breakdown (4) • Patients for whom there is cause for arrest or delay in tablet passage through the gastrointestinal tract such as those suffering from delayed gastric emptying, esophageal compression, intestinal obstruction or stricture (4) • Patients with peptic ulcer disease (4) • Patients with active urinary tract infection (4) • Patients with renal insufficiency (glomerular filtration rate of less than 0.7 ml/kg/min) (4) -----------------------WARNINGS AND PRECAUTIONS----------------------- • Hyperkalemia: In patients with impaired mechanisms for excreting potassium, Urocit®-K administration can produce hyperkalemia and cardiac arrest. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Urocit®-K in patients with chronic renal failure, or any other condition which impairs potassium excretion such as severe myocardial damage or heart failure, should be avoided (5.1) • Gastrointestinal lesions: if there is severe vomiting, abdominal pain or gastrointestinal bleeding, Urocit®-K should be discontinued immediately and the possibility of bowel perforation or obstruction investigated (5.2) ------------------------------ADVERSE REACTIONS------------------------------- Some patients may develop minor gastrointestinal complaints such as abdominal discomfort, vomiting, diarrhea, loose bowel movements or nausea. These may be alleviated by taking the dose with meals or snacks or by reducing the dosage (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at 1-800-298-1087 or FDA at 1-800-FDA 1088 or www.fda.gov/medwatch ------------------------------DRUG INTERACTIONS------------------------------- The following drug interactions may occur with potassium citrate: • Potassium-sparing diuretics: concomitant administration should be avoided since the simultaneous administration of these agents can produce severe hyperkalemia (7.1) • Drugs that slow gastrointestinal transit time: These agents (such as anticholinergics) can be expected to increase the gastrointestinal irritation produced by potassium salts (7.2) -----------------------USE IN SPECIFIC POPULATIONS------------------------ • Pregnant women: Pregnancy Category C; animal reproduction studies have not been conducted. It is not known whether Urocit®-K can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Urocit®-K should be given to a pregnant woman only if clearly needed (8.1) • Nursing mothers: The normal potassium ion content of human milk is about 13 mEq/L. It is not known if Urocit®-K has an effect on this content. Urocit®-K should be given to a woman who is breast feeding only if clearly needed (8.3) • Pediatric Use: Safety and effectiveness in children have not been established (8.4) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2009 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Renal tubular acidosis (RTA) with calcium stones 1.2 Hypocitraturic calcium oxalate nephrolithiasis of any etiology 1.3 Uric acid lithiasis with or without calcium stones 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions 2.2 Severe hypocitraturia 2.3 Mild to moderate hypocitraturia 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hyperkalemia 5.2 Gastrointestinal lesions 6 ADVERSE REACTIONS 6.1 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Potential Effects of Potassium citrate on Other Drugs 7.2 Potential Effects of Other Drugs on Potassium citrate 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 14 CLINICAL STUDIES 14.1 Renal tubular acidosis (RTA) with calcium stones 14.2 Hypocitraturic calcium oxalate nephrolithiasis of any etiology 14.3 Uric acid lithiasis with or without calcium stones 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Administration of Drug Sections or subsections omitted from the full prescribing information are not listed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Renal tubular acidosis (RTA) with calcium stones Potassium citrate is indicated for the management of renal tubular acidosis [see Clinical Studies (14.1)]. 1.2 Hypocitraturic calcium oxalate nephrolithiasis of any etiology Potassium citrate is indicated for the management of Hypocitraturic calcium oxalate nephrolithiasis [see Clinical Studies (14.2)]. 1.3 Uric acid lithiasis with or without calcium stones Potassium citrate is indicated for the management of Uric acid lithiasis with or without calcium stones [see Clinical Studies (14.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions Treatment with extended release potassium citrate should be added to a regimen that limits salt intake (avoidance of foods with high salt content and of added salt at the table) and encourages high fluid intake (urine volume should be at least two liters per day). The objective of treatment with Urocit®-K is to provide Urocit®-K in sufficient dosage to restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6.0 or 7.0. Monitor serum electrolytes (sodium, potassium, chloride and carbon dioxide), serum creatinine and complete blood counts every four months and more frequently in patients with cardiac disease, renal disease or acidosis. Perform electrocardiograms periodically. Treatment should be discontinued if there is hyperkalemia, a significant rise in serum creatinine or a significant fall in blood hemocrit or hemoglobin. 2.2 Severe Hypocitraturia In patients with severe hypocitraturia (urinary citrate < 150 mg/day), therapy should be initiated at a dosage of 60 mEq /day (30 mEq two times/day or 20 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. In addition, urinary citrate and/or pH should be measured every four months. Doses of Urocit®-K greater than 100 mEq/day have not been studied and should be avoided. 2.3 Mild to Moderate Hypocitraturia In patients with mild to moderate hypocitraturia (urinary citrate > 150 mg/day) therapy should be initiated at 30 mEq/day (15 mEq two times/day or 10 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. Doses of Urocit®-K greater than 100 mEq/day have not been studied and should be avoided. 3 DOSAGE FORMS AND STRENGTHS • 5 mEq tablets are uncoated, tan to yellowish in color, modified ball shaped, with MPC 600 debossed on one side and blank on the other • 10 mEq tablets are uncoated, tan to yellowish in color, elliptical shaped, with 610 debossed on one side and MISSION on the other • 15 mEq tablets are uncoated, tan to yellowish in color, modified rectangle shaped, with M15 debossed on one side and blank on the other 4 CONTRAINDICATIONS Urocit®-K is contraindicated: • In patients with hyperkalemia (or who have conditions pre-disposing them to hyperkalemia), as a further rise in serum potassium concentration may produce cardiac arrest. Such conditions include: chronic renal failure, uncontrolled diabetes mellitus, acute dehydration, strenuous physical exercise in unconditioned individuals, adrenal insufficiency, extensive tissue breakdown or the administration of a potassium-sparing agent (such as triamterene, spironolactone or amiloride). • In patients in whom there is cause for arrest or delay in tablet passage through the gastrointestinal tract, such as those suffering from delayed gastric emptying, esophageal compression, intestinal obstruction or pH resulting from Urocit®-K therapy might promote further bacterial growth. • In patients with renal insufficiency (glomerular filtration rate of less than 0.7 ml/kg/min), because of the danger of soft tissue calcification and increased risk for the development of hyperkalemia. 5 WARNINGS AND PRECAUTIONS 5.1 Hyperkalemia In patients with impaired mechanisms for excreting potassium, Urocit®-K administration can produce hyperkalemia and cardiac arrest. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Urocit®-K in patients with chronic renal failure, or any other condition which impairs potassium excretion such as severe myocardial damage or heart failure, should be avoided. Closely monitor for signs of hyperkalemia with periodic blood tests and ECGs. 5.2 Gastrointestinal Lesions Because of reports of upper gastrointestinal mucosal lesions following administration of potassium-chloride (wax-matrix), an endoscopic examination of the upper gastrointestinal mucosa was performed in 30 normal volunteers after they had taken glycopyrrolate 2 mg p.o. t.i.d., Urocit®-K 95 mEq/day, wax-matrix potassium chloride 96 mEq/day or wax-matrix placebo, in thrice daily schedule in the fasting state for one week. Urocit®-K and the wax-matrix formulation of potassium chloride were indistinguishable but both were significantly more irritating than the wax-matrix placebo. In a subsequent, similar study, lesions were less severe when glycopyrrolate was omitted. Solid dosage forms of potassium chlorides have produced stenotic and/or ulcerative lesions of the small bowel and deaths. These lesions are caused by a high local concentration of potassium ions in the region of the dissolving tablets, which injured the bowel. In addition, perhaps because wax-matrix preparations are not enteric-coated and release some of their potassium content in the stomach, there have been reports of upper gastrointestinal bleeding associated with these products. The frequency of gastrointestinal lesions with wax-matrix potassium chloride products is estimated at one per 100,000 patient-years. Experience with Urocit®-K is limited, but a similar frequency of gastrointestinal lesions should be anticipated. If there is severe vomiting, abdominal pain or gastrointestinal bleeding, Urocit®-K should be discontinued immediately and the possibility of bowel perforation or obstruction investigated. 6 ADVERSE REACTIONS 6.1 Postmarketing Experience Some patients may develop minor gastrointestinal complaints during Urocit®-K therapy, such as abdominal discomfort, vomiting, diarrhea, loose bowel movements or nausea. These symptoms are due to the irritation of the gastrointestinal tract, and may be alleviated by taking the dose with meals or snacks, or by reducing the dosage. Patients may find intact matrices in their feces. 7 DRUG INTERACTIONS 7.1 Potential Effects of Potassium citrate on Other Drugs Potassium-sparing Diuretics: Concomitant administration of Urocit®-K and a potassium-sparing diuretic (such as triamterene, spironolactone or amiloride) should be avoided since the simultaneous administration of these agents can produce severe hyperkalemia. 7.2 Potential Effects of Other Drugs on Potassium citrate Drugs that slow gastrointestinal transit time: These agents (such as anticholinergics) can be expected to increase the gastrointestinal irritation produced by potassium salts. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted. It is also not known whether Urocit®-K can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Urocit®-K should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers The normal potassium ion content of human milk is about 13 mEq/L. It is not known if Urocit®-K has an effect on this content. Urocit®-K should be stricture, or those taking anticholinergic medication. given to a woman who is breast feeding only if clearly needed. • In patients with peptic ulcer disease because of its ulcerogenic potential. 8.4 Pediatric Use • In patients with active urinary tract infection (with either urea-splitting Safety and effectiveness in children have not been established. or other organisms, in association with either calcium or struvite stones). The ability of Urocit®-K to increase urinary citrate may be attenuated by bacterial enzymatic degradation of citrate. Moreover, the rise in urinary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 OVERDOSAGE Treatment of Overdosage: The administration of potassium salts to persons without predisposing conditions for hyperkalemia rarely causes serious hyperkalemia at recommended dosages. It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration and characteristic electrocardiographic changes (peaking of T-wave, loss of P-wave, depression of S-T segment and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest. Treatment measures for hyperkalemia include the following: 1. Patients should be closely monitored for arrhythmias and electrolyte changes. 2. Elimination of medications containing potassium and of agents with potassium sparing properties such as potassium-sparing diuretics, ARBs, ACE inhibitors, NSAIDs, certain nutritional supplements and many others. 3. Elimination of foods containing high levels of potassium such as almonds, apricots, bananas, beans (lima, pinto, white), cantaloupe, carrot juice (canned), figs, grapefruit juice, halibut, milk, oat bran, potato (with skin), salmon, spinach, tuna and many others. 4. Intravenous calcium gluconate if the patient is at no risk or low risk of developing digitalis toxicity. 5. Intravenous administration of 300-500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL. 6. Correction of acidosis, if present, with intravenous sodium bicarbonate. 7. Hemodialysis or peritoneal dialysis. 8. Exchange resins may be used. However, this measure alone is not sufficient for the acute treatment of hyperkalemia. Lowering potassium levels too rapidly in patients taking digitalis can produce digitalis toxicity. 11 DESCRIPTION Urocit®-K is a citrate salt of potassium. Its empirical formula is K3C6H507 • H20, and it has the following chemical structure: CH2 COOK HO C COOK • H2O CH2 COOK Urocit®-K yellowish to tan, oral wax-matrix tablets, contain 5 mEq (540 mg) potassium citrate, 10 mEq (1080 mg) potassium citrate and 15 mEq (1620 mg) potassium citrate each. Inactive ingredients include carnauba wax and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action When Urocit®-K is given orally, the metabolism of absorbed citrate produces an alkaline load. The induced alkaline load in turn increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafilterable serum citrate. Thus, Urocit®-K therapy appears to increase urinary citrate principally by modifying the renal handling of citrate, rather than by increasing the filtered load of citrate. The increased filtered load of citrate may play some role, however, as in small comparisons of oral citrate and oral bicarbonate, citrate had a greater effect on urinary citrate. In addition to raising urinary pH and citrate, Urocit®-K increases urinary potassium by approximately the amount contained in the medication. In some patients, Urocit®-K causes a transient reduction in urinary calcium. The changes induced by Urocit®-K produce urine that is less conducive to the crystallization of stone-forming salts (calcium oxalate, calcium phosphate and uric acid). Increased citrate in the urine, by complexing with calcium, decreases calcium ion activity and thus the saturation of calcium oxalate. Citrate also inhibits the spontaneous nucleation of calcium oxalate and calcium phosphate (brushite). The increase in urinary pH also decreases calcium ion activity by increasing calcium complexation to dissociated anions. The rise in urinary pH also increases the ionization of uric acid to the more soluble urate ion. Urocit®-K therapy does not alter the urinary saturation of calcium phosphate, since the effect of increased citrate complexation of calcium is opposed by the rise in pH-dependent dissociation of phosphate. Calcium phosphate stones are more stable in alkaline urine. In the setting of normal renal function, the rise in urinary citrate following a single dose begins by the first hour and lasts for 12 hours. With multiple doses the rise in citrate excretion reaches its peak by the third day and averts the normally wide circadian fluctuation in urinary citrate, thus maintaining urinary citrate at a higher, more constant level throughout the day. When the treatment is withdrawn, urinary citrate begins to decline toward the pre treatment level on the first day. The rise in citrate excretion is directly dependent on the Urocit®-K dosage. Following long-term treatment, Urocit®-K at a dosage of 60 mEq/day raises urinary citrate by approximately 400 mg/day and increases urinary pH by approximately 0.7 units. In patients with severe renal tubular acidosis or chronic diarrheal syndrome where urinary citrate may be very low (<100 mg/day), Urocit®-K may be relatively ineffective in raising urinary citrate. A higher dose of Urocit®-K may therefore be required to produce a satisfactory citraturic response. In patients with renal tubular acidosis in whom urinary pH may be high, Urocit®-K produces a relatively small rise in urinary pH. 14 CLINICAL STUDIES The pivotal Urocit®-K trials were non-randomized and non-placebo controlled where dietary management may have changed coincidentally with pharmacological treatment. Therefore, the results as presented in the following sections may overstate the effectiveness of the product. 14.1 Renal tubular acidosis (RTA) with calcium stones The effect of oral potassium citrate therapy in a non-randomized, non- placebo controlled clinical study of five men and four women with calcium oxalate/calcium phosphate nephrolithiasis and documented incomplete distal renal tubular acidosis was examined. The main inclusion criterion was a history of stone passage or surgical removal of stones during the 3 years prior to initiation of potassium citrate therapy. All patients began alkali treatment with 60-80 mEq potassium citrate daily in 3 or 4 divided doses. Throughout treatment, patients were instructed to stay on a sodium restricted diet (100 mEq/day) and to reduce oxalate intake (limited intake of nuts, dark roughage, chocolate and tea). A moderate calcium restriction (400-800 mg/day) was imposed on patients with hypercalciuria. X-rays of the urinary tract, available in all patients, were reviewed to determine presence of pre-existing stones, appearance of new stones, or change in the number of stones. Potassium citrate therapy was associated with inhibition of new stone formation in patients with distal tubular acidosis. Three of the nine patients continued to pass stones during the on-treatment phase. While it is likely that these patients passed preexisting stones during therapy, the most conservative assumption is that the passed stones were newly formed. Using this assumption, the stone-passage remission rate was 67%. All patients had a reduced stone formation rate. Over the first 2 years of treatment, the on- treatment stone formation rate was reduced from 13±27 to 1±2 per year. 14.2 Hypocitraturic calcium oxalate nephrolithiasis of any etiology Eighty-nine patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis with or without calcium nephrolithiasis participated in this non- randomized, non-placebo controlled clinical study. Four groups of patients were treated with potassium citrate: Group 1 was comprised of 19 patients, 10 with renal tubular acidosis and 9 with chronic diarrheal syndrome, Group 2 was comprised of 37 patients, 5 with uric acid stones alone, 6 with uric acid lithiasis and calcium stones, 3 with type 1 absorptive hypercalciuria, 9 with type 2 absorptive hypercalciuria and 14 with hypocitraturia. Group 3 was comprised of 15 patients with history of relapse on other therapy and Group 4 was comprised of 18 patients, 9 with type 1 absorptive hypercalciuria and calcium stones, 1 with type 2 absorptive hypercalciuria and calcium stones, 2 with hyperuricosuric calcium oxalate nephrolithiasis, 4 with uric acid lithiasis accompanied by calcium stones and 2 with hypocitraturia and hyperuricemia accompanied by calcium stones. The dose of potassium citrate ranged from 30 to 100 mEq per day, and usually was 20 mEq administered orally 3 times daily. Patients were followed in an outpatient setting every 4 months during treatment and were studied over a period from 1 to 4.33 years. A three-year retrospective pre-study history for stone passage or removal was obtained and corroborated by medical records. Concomitant therapy (with thiazide or allopurinol) was allowed if patients had hypercalciuria, hyperuricosuria or hyperuricemia. Group 2 was treated with potassium citrate alone. In all groups, treatment that included potassium citrate was associated with a sustained increase in urinary citrate excretion from subnormal values to normal values (400 to 700 mg/day), and a sustained increase in urinary pH from 5.6-6.0 to approximately 6.5. The stone formation rate was reduced in all groups as shown in Table 1. Table 1. Effect of Urocit®-K In Patients With Calcium Oxalate Nephrolithiasis. Stones Formed Per Year Group Baseline On Treatment Remission Any Decrease I (n=19) 12 ± 30 0.9 ± 1.3 58% 95% II (n=37) 1.2 ± 2 0.4 ± 1.5 89% 97% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda III (n=15) 4.2 ± 7 0.7 ± 2 67% 100% IV (n=18) 3.4 ± 8 0.5 ± 2 94% 100% Total (n=89) 4.3 ±15 0.6 ± 2 80% 98% * Remission defined as “the percentage of patients remaining free of newly formed stones during treatment”. 14.3 Uric acid lithiasis with or without calcium stones A long-term non-randomized, non-placebo controlled clinical trial with eighteen adult patients with uric acid lithiasis participated in the study. Six patients formed only uric acid stones, and the remaining 12 patients formed mixed stones containing both uric acid and calcium salts or formed both uric acid stones (without calcium salts) and calcium stones (without uric acid ) on separate occasions. Eleven of the 18 patients received potassium citrate alone. Six of the 7 other patients also received allopurinol for hyperuricemia with gouty arthritis, symptomatic hyperuricemia, or hyperuricosuria. One patient also received hydrochlorothiazide because of unclassified hypercalciuria. The main inclusion criterion was a history of stone passage or surgical removal of stones during the 3 years prior to initiation of potassium citrate therapy. All patients received potassium citrate at a dosage of 30-80 mEq/day in three-to-four divided doses and were followed every four months for up to 5 years. While on potassium citrate treatment, urinary pH rose significantly from a low value of 5.3 ± 0.3 to within normal limits (6.2 to 6.5). Urinary citrate which was low before treatment rose to the high normal range and only one stone was formed in the entire group of 18 patients. 15 REFERENCES 1. Pak, C. (1987). Citrate and Renal Calculi. Mineral and Electrolyte Metabolism 13, 257-266. 2. Pak, C. (1985). Long-Term Treatment of Calcium Nephrolithiasis with Potassium Citrate. The Journal of Urology 134, 11-19. 3. Preminger, G.M., K. Sakhaee, C. Skurla and C.Y.C. Pak. (1985). Prevention of Recurrent Calcium Stone Formation with Potassium Citrate therapy in Patients with Distal Renal Tubular Acidosis. The Journal of Urology 134, 20-23. 4. Pak, C.Y.C., K. Sakhaee and C. Fuller. (1986). Successful Management of Uric Acid Nephrolithiasis with Potassium Citrate. Kidney International 30, 422-428. 5. Hollander-Rodriguez, J et al. (2006). Hyperkalemia, American Family Physician, Vol.73/No. 2. 6. Greenberg, A et al. (1998). Hyperkalemia: treatment options. Semen Nephrol. Jan; 18 (1): 46-57. 16 HOW SUPPLIED/STORAGE AND HANDLING Urocit®-K 5 mEq tablets are uncoated, tan to yellowish in color, modified ball shaped, with MPC 600 debossed on one side and blank on the other, supplied in bottles as: NDC 0178-0600-01 Bottle of 100 Urocit®-K 10 mEq tablets are uncoated, tan to yellowish in color, elliptical shaped, with MPC 610 debossed on one side and MISSION on the other, supplied in bottles as: NDC 0178-0610-01 Bottle of 100 Urocit®-K 15 mEq tablets are uncoated, tan to yellowish in color, modified rectangle shaped, with M15 debossed on one side and blank on the other, supplied in bottles as: NDC 0178-0615-01 Bottle of 100 Storage: Store in a tight container. 17 PATIENT COUNSELING INFORMATION 17.1 Administration of Drug Tell patients to take each dose without crushing, chewing or sucking the tablet. Tell patients to take this medicine only as directed. This is especially important if the patient is also taking both diuretics and digitalis preparations. Tell patients to check with the doctor if there is trouble swallowing tablets or if the tablet seems to stick in the throat. Tell patients to check with the doctor at once if tarry stools or other evidence of gastrointestinal bleeding is noticed. Tell patients that their doctor will perform regular blood tests and electrocardiograms to ensure safety. L061501 C01 Rev 012090 MISSION PHARMACAL COMPANY SAN ANTONIO, TX USA 78230 1355 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.017657	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019071s012lbl.pdf', 'application_number': 19071, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,433	NDA 19-079/S-024 Page 3 Flarex (fluorometholone acetate ophthalmic suspension) Sterile DESCRIPTION: FLAREX® (fluorometholone acetate ophthalmic suspension) is a corticosteroid prepared as a sterile topical ophthalmic suspension. The active ingredient, fluorometholone acetate, is a white to creamy white powder with an empirical formula of C24H31F05 and a molecular weight of 418.5. Its chemical name is 9-fluoro-11β, 17-dihydroxy-6α -methylpregna-1, 4-diene-3, 20-dione 17-acetate. The chemical structure of Fluorometholone Acetate is presented below: [structure] Each mL contains: Active: fluorometholone acetate 1 mg (0.1%). Preservative: benzalkonium chloride 0.01 %. Inactives: sodium chloride, monobasic sodium phosphate, edetate disodium, hydroxyethyl cellulose, tyloxapol, hydrochloric acid and/or sodium hydroxide (to adjust pH), and purified water. The pH of the suspension is approximately 7.3, with an osmolality of approximately 300 mOsm/kg. CLINICAL PHARMACOLOGY: Corticosteroids suppress the inflammatory response to inciting agents of mechanical, chemical or immunological nature. No generally accepted explanation of this steroid property has been advanced. Corticosteroids cause a rise in intraocular pressure in susceptible individuals. In a small study, FLAREX (fluorometholone acetate ophthalmic suspension) demonstrated a significantly longer average time to produce a rise in intraocular pressure than did dexamethasone phosphate; however, the ultimate magnitude of the rise was equivalent for both drugs and in a small percentage of individuals a significant rise in intraocular pressure occurred within three days. INDICATIONS AND USAGE: FLAREX (fluorometholone acetate ophthalmic suspension) is indicated for use in the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the eye. CONTRAINDICATIONS: Contraindicated in acute superficial herpes simplex keratitis, vaccinia, varicella, and most other viral diseases of cornea and conjunctiva; tuberculosis; fungal diseases; acute purulent untreated infections, which like other diseases caused by microorganisms, may be masked or enhanced by the presence of the steroid; and in those persons who have known hypersensitivity to any component of this preparation. WARNINGS: FOR TOPICAL OPHTHALMIC USE ONLY. NOT FOR INJECTION. Use in the treatment of herpes simplex infection requires great caution. Prolonged use may result in glaucoma, damage to the optic nerve, defect in visual acuity and visual field, cataract formation and/or may aid in the establishment of secondary ocular infections from pathogens due to suppression of host response. Acute purulent infections of the eye may be masked or exacerbated by presence of steroid medication. In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with chronic use of topical steroids. It is advisable that the intraocular pressure be checked frequently. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-079/S-024 Page 4 PRECAUTIONS: General: Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Information for Patients: Do not touch dropper tip to any surface, as this may contaminate the suspension. The preservative in FLAREX® (fluorometholone acetate ophthalmic suspension), benzalkonium chloride, may be absorbed by soft contact lenses. FLAREX (fluorometholone acetate ophthalmic suspension) should not be administered while wearing soft contact lenses. Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals or in humans to evaluate the possibility of these effects with fluorometholone. Pregnancy: Pregnancy Category C. Fluorometholone has been shown to be embryocidal and teratogenic in rabbits when administered at low multiples of the human ocular dose. Fluorometholone was applied ocularly to rabbits daily on days 6-18 of gestation, and dose related fetal loss and fetal abnormalities including cleft palate, deformed rib cage, anomalous limbs and neural abnormalities such as encephalocele, craniorachischisis, and spina bifida were observed. There are no adequate and well controlled studies of fluorometholone in pregnant women, and it is not known whether fluorometholone can cause fetal harm when administered to a pregnant woman. Fluorometholone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLAREX® (fluorometholone acetate ophthalmic suspension), is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS: Glaucoma with optic nerve damage, visual acuity and field defects, cataract formation, secondary ocular infection following suppression of host response, and perforation of the globe may occur. DOSAGE AND ADMINISTRATION: Shake Well Before Using. One to two drops instilled into the conjunctival sac(s) four times daily. During the initial 24 to 48 hours the dosage may be safely increased to two drops every two hours. If no improvement after two weeks, consult physician. Care should be taken not to discontinue therapy prematurely. HOW SUPPLIED: FLAREX® Suspension is supplied in white low density polyethylene (LDPE) bottles, with natural LDPE dispensing plugs and pink polypropylene closures. The product is supplied as 5 mL in an 8 mL bottle, and 10 mL in a 10 mL bottle. 5 mL: NDC 0065-0096-05 10 ml: NDC 0065-0096-10 STORAGE: Store upright between 2°-25°C (36°-77°F). Protect from freezing. Rx Only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-079/S-024 Page 5 ©2002, 2004 Alcon, Inc. Alcon ® ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA Revised: April 2004 Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-079/S-024 Page 6 Carton Label for 5 mL: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-079/S-024 Page 7 Carton Label for 10 mL: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-079/S-024 Page 8 Container label for 5 mL: Container label for 10 mL: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.304328	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019079s024lbl.pdf', 'application_number': 19079, 'submission_type': 'SUPPL ', 'submission_number': 24}
11,434	NDA 19-081/S-036/039 Page 4 Estraderm® estradiol transdermal system Continuous delivery for twice-weekly application Rx only Prescribing Information ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is currently no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen dose. CARDIOVASCULAR AND OTHER RISKS Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of conjugated estrogens with medroxyprogesterone, and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 5 DESCRIPTION Estraderm, estradiol transdermal system, is designed to release estradiol through a rate-limiting membrane continuously upon application to intact skin. Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradiol per day via skin of average permeability (interindividual variation in skin permeability is approximately 20%). Each corresponding system having an active surface area of 10 or 20 cm2 contains 4 or 8 mg of estradiol USP and 0.3 or 0.6 mL of alcohol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17ß- diol. The structural formula is HO H H H H CH3 OH The Estraderm system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. Alcohol is also released from the system during use. CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 6 Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. They vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. In a study using transdermally administered estradiol, 0.1 mg daily, plasma levels increased by 66 pg/mL, resulting in an average plasma level of 73 pg/mL. There were no significant increases in the concentration of renin substrate or other hepatic proteins (sex hormone-binding globulin, thyroxine- binding globulin, and corticosteroid-binding globulin). Pharmacokinetics The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Absorption Administration of Estraderm produces mean serum concentrations of estradiol comparable to those produced by daily oral administration of estradiol at about 20 times the daily transdermal dose. In single-application studies in 14 postmenopausal women using Estraderm systems that provided 0.05 and 0.1 mg of exogenous estradiol per day, these systems produced increased blood levels within 4 hours and maintained respective mean serum estradiol concentrations of 32 and 67 pg/mL above baseline over the application period. At the same time, increases in estrone serum concentration averaged only 9 and 27 pg/mL above baseline, respectively. Serum concentrations of estradiol and estrone returned to preapplication levels within 24 hours after removal of the system. The estimated daily urinary output of estradiol conjugates increased 5 to 10 times the baseline values and returned to near baseline within 2 days after removal of the system. By comparison, estradiol (2 mg/day) administered orally to postmenopausal women resulted in increases in mean serum concentration of 59 pg/mL of estradiol and 302 pg/mL of estrone above baseline on the third consecutive day of dosing. Urinary output of estradiol conjugates after oral administration increased to about 100 times the baseline values and did not approach baseline until 7-8 days after the last dose. In a 3-week multiple-application study of 14 postmenopausal women in which Estraderm 0.05 was applied twice weekly, the mean increments in steady-state serum concentration were 30 pg/mL for estradiol and 12 pg/mL for estrone. Urinary output of estradiol conjugates returned to baseline within 3 days after removal of the last (6th) system, indicating little or no estrogen accumulation in the body. Distribution No specific investigation of the tissue distribution of estradiol absorbed from Estraderm in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 7 Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Transdermal administration produces therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Because estradiol has a short half-life (~1 hour), transdermal administration of estradiol allows a rapid decline in blood levels after an Estraderm system is removed, e.g., in a cycling regimen. Special Populations Estraderm was only investigated in postmenopausal women. Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of the use of 0.625 mg conjugated equine estrogens (CE) per day alone and of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA substudy, which included 16,608 women (average age of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 8 63 years, range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below. Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa Placebo n= 8102 CE/MPA n= 8506 Eventc Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI) Absolute Risk per 10,000 person-years CHD events Non-fatal MI CHD death 1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97) 30 23 6 37 30 7 Invasive breast cancerb 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global indexc 1.15 (1.03-1.28) 151 170 Deep vein thrombosisd 2.07 (1.49-2.87) 13 26 Vertebral fracturesd 0.66 (0.44-0.98) 15 9 Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131 a adapted from JAMA, 2002: 288: 321-333 b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. d not included in Global index nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 9 was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) INDICATIONS AND USAGE Estraderm® (estradiol transdermal system) is indicated in: 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. 5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. Estraderm® (estradiol transdermal system) should not be used in patients with known hypersensitivity to its ingredients. 7. Known or suspected pregnancy. There is no indication for Estraderm in pregnancy. There appears to be little or no increased risk of birth defects in women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS). WARNINGS See BOXED WARNINGS. The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 10 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for cardiovascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE alone compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and in the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE) In the Women’s Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 11 If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the CE/MPA substudy of the Women’s Health Initiative study (WHI), a 26% increase of invasive breast cancer (38 vs 30 per 10,000 woman-years) after an average of 5.2 years of treatment was observed in women receiving CE/MPA compared to women receiving placebo. The increased risk of breast cancer became apparent after 4 years on CE/MPA. The women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with CE/MPA than those who had never used these hormones. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the WHI, no increased risk of breast cancer in CE-treated women compared to placebo was reported after an average of 5.2 years of therapy. These data are preliminary and that substudy of WHI is continuing. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens with or without a progestin. This association was reanalyzed in original data from 51 studies that involved various doses and types of estrogens, with and without progestins. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for 5 years or longer. Some later studies have suggested that postmenopausal treatment with estrogens and progestin increase the risk of breast cancer more than treatment with estrogen alone. A postmenopausal woman without a uterus who requires estrogen should receive estrogen- alone therapy, and should not be exposed unnecessarily to progestins. All postmenopausal women should receive yearly breast exams by a health care provider and perform monthly This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 12 breast self-examinations. In addition, mammography examinations should be scheduled as suggested by providers based on patient age and risk factors. 3. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 4. Hypercalcemia Administration of estrogen may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. 5. Visual abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued. PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Familial hyperlipoproteinemia. In patients with familial defects of lipoprotein metabolism, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function. Although transdermally administered estrogen therapy avoids first- pass hepatic metabolism, estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 13 range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention. Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Ovarian cancer. Use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with estrogen/progestin combination therapy in postmenopausal women. 9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogen therapy. 10. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria and should be used with caution in women with these conditions. B. Patient Information. Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Estraderm. C. Laboratory Tests. Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH). D. Drug/Laboratory Test Interactions. 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 14 concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. E. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. (See BOXED WARNINGS, CONTRAINDICATIONS, and WARNINGS.) F. Pregnancy. Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Estraderm is administered to a nursing woman. H. Pediatric Use. Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. (See INDICATIONS and DOSAGE AND ADMINISTRATION.) I. Geriatric Use. Clinical studies of Estraderm did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 15 ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS and PRECAUTIONS. The most commonly reported adverse reaction to Estraderm in clinical trials was redness and irritation at the application site. This occurred in about 17% of the women treated and caused approximately 2% to discontinue therapy. Reports of rash have been rare. There have also been rare reports of severe systemic allergic reactions. The following additional adverse reactions have been reported with estrogens: 1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2. Breasts. Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular. Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gall bladder disease; pancreatitis. 5. Skin. Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes. Retinal vascular thrombosis; steepening of corneal curvature; intolerance to contact lenses. 7. Central nervous system. Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy. 8. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides. OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of estrogen- containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 16 DOSAGE AND ADMINISTRATION The adhesive side of the Estraderm system should be placed on a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Estraderm should not be applied to the breasts. The Estraderm system should be replaced twice weekly. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off. The system should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the unlikely event that a system should fall off, the same system may be reapplied. If necessary, a new system may be applied. In either case, the original treatment schedule should be continued. Initiation of Therapy When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g. 3-month to 6-month intervals) to determine whether treatment is still necessary (See BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Estraderm is currently available in two dosage forms – 0.05 mg and 0.1 mg. Patients should be started at the lowest dose. For treatment of moderate to severe vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause, initiate therapy with Estraderm 0.05 applied to the skin twice weekly. Prophylactic therapy with Estraderm to prevent postmenopausal bone loss should be initiated with the 0.05 mg/day dosage as soon as possible after menopause. The dosage may be adjusted if necessary. Discontinuation of estrogen therapy may reestablish bone loss at a rate comparable to the immediate postmenopausal period. In women not currently taking oral estrogens, treatment with Estraderm may be initiated at once. In women who are currently taking oral estrogen, treatment with Estraderm should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. Therapeutic Regimen Estraderm therapy may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Estraderm may be given on a cyclic schedule (e.g., 3 weeks on drug followed by 1 week off drug). HOW SUPPLIED Estraderm estradiol transdermal system 0.05 mg/day – each 10 cm2 system contains 4 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 17 Patient Calendar Pack of 8 Systems ..................................................NDC 0083-2310-08 Carton of 6 Patient Calendar Packs of 8 Systems..............................NDC 0083-2310-62 Carton of 1 Patient Calendar Pack of 24 Systems .............................NDC 0083-2310-24 Estraderm estradiol transdermal system 0.1 mg/day – each 20 cm2 system contains 8 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems ..................................................NDC 0083-2320-08 Carton of 6 Patient Calendar Packs of 8 Systems..............................NDC 0083-2320-62 Carton of 1 Patient Calendar Pack of 24 Systems .............................NDC 0083-2320-24 ____________________ *See DESCRIPTION. Do not store above 30°C (86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch. REV: APRIL 2004 PATIENT INFORMATION Estraderm® (estradiol transdermal system) Read this PATIENT INFORMATION before you start taking Estraderm®(estradiol transdermal system) and read all the information that you get each time you refill Estraderm. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. What is the most important information I should know about Estraderm (an estrogen hormone)? • Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. You and your health care provider should talk regularly about whether you still need treatment with Estraderm. What is Estraderm®? Estraderm is a patch that contains the estrogen hormone, estradiol. When applied to the skin as directed below, Estraderm releases estrogen through the skin into the bloodstream. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 18 What is Estraderm used for? Estraderm is used after menopause to: • reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your health care provider should talk regularly about whether you still need treatment with Estraderm. • treat moderate to severe dryness, itching and burning in or around the vagina. You and your health care provider should talk regularly about whether you still need treatment with Estraderm to control these problems. • treat certain conditions in which a young woman’s ovaries do not produce enough estrogens naturally. • help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estraderm only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrogens might be better for you. You and your health care provider should talk regularly about whether you should continue with Estraderm. Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your health care provider before starting them. Who should not take Estraderm? Do not start taking Estraderm if you: • have unusual vaginal bleeding. • currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take Estraderm. • had a stroke or heart attack in the recent past (for example in the past year). • currently have or have had blood clots. • are allergic to Estraderm or any of its ingredients. See the end of this leaflet for a list of ingredients in Estraderm. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 19 • think you may be, or know that you are, pregnant. Tell your health care provider: • if you are breastfeeding. The hormone in Estraderm can pass into your milk. • about all of your medical problems: Your health care provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Estraderm works. Estraderm may also affect how other medicines work. • if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens. How should I take Estraderm? Estrogens should be used only as long as needed and at the lowest possible dose that works. You and your health care provider should talk regularly (for example every 3 to 6 months) about whether you still need treatment with Estraderm. How and Where to Apply Estraderm Each Estraderm system is individually sealed in a protective pouch. Tear open this pouch at the indentation (do not use scissors) and remove the system. Bubbles in the system are normal. A stiff protective liner covers the adhesive side of the system — the side that will be placed against your skin. This liner must be removed before applying the system. Slide the protective liner sideways between your thumb and index finger. Then hold the system at one edge. Remove the protective liner and discard it. Try to avoid touching the adhesive. Apply the adhesive side of the system to a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Some women may find that it is more comfortable to wear Estraderm on the buttocks. Do not apply Estraderm to your breasts. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 20 removing the protective liner. Press the system firmly in place with the palm of your hand for about 10 seconds, making sure there is good contact, especially around the edges. The Estraderm system should be worn continuously until it is time to replace it with a new system. You may wish to experiment with different locations when applying a new system, to find ones that are most comfortable for you and where clothing will not rub on the system. When to Apply Estraderm The Estraderm system should be replaced twice weekly. Your Estraderm package contains a calendar checklist on the back to help you remember a schedule. Mark the 2-day schedule you plan to follow. Always change the system on the 2 days of the week you have marked. When changing the system, remove the used Estraderm and discard it. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Estraderm on a different skin site. (The same skin site should not be used again for at least 1 week after removal of the system.) Please note: Contact with water when you are bathing, swimming, or showering will not affect the system. In the unlikely event that a system should fall off, put this same system back on and continue to follow your original treatment schedule. If necessary, you may apply a new system but continue to follow your original schedule. What are the possible side effects of estrogens? Less common but serious side effects include: ---- Breast cancer ---- Cancer of the uterus ---- Stroke ---- Heart attack ---- Blood clots ---- Gallbladder disease. ---- Ovarian cancer These are some of the warning signs of serious side effects: ---- Breast lumps. ---- Unusual vaginal bleeding. ---- Dizziness and faintness ---- Changes in speech ---- Severe headaches ---- Chest pain ---- Shortness of breath ---- Pains in your legs ---- Changes in vision This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 21 ---- Vomiting Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you Common side effects include: ---- Headache ---- Breast pain ---- Irregular vaginal bleeding or spotting ---- Stomach/abdominal cramps, bloating ---- Nausea and vomiting ---- Hair loss Other side effects include: ---- High blood pressure ---- Liver problems ---- High blood sugar ---- Fluid retention ---- Enlargement of benign tumors of the uterus (“fibroids”) ---- Vaginal yeast infection Other side effects of Estraderm may be possible. If you have questions, talk to your health care provider or pharmacist. What can I do to lower my chances of a serious side effect with Estraderm? • Talk with your health care provider regularly about whether you should continue taking Estraderm. • See your health care provider right away if you get vaginal bleeding while taking Estraderm. • Have a breast exam and mammogram (breast X-ray) every year unless your health care provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your health care provider for ways to lower your chances for getting heart disease. General information about safe and effective use of Estraderm This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-036/039 Page 22 Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Estraderm for conditions for which it was not prescribed. Do not give Estraderm to other people, even if they have the same symptoms you have. It may harm them. Keep Estraderm out of the reach of children. This leaflet provides a summary of the most important information about Estraderm. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Estraderm that is written for health professionals. You can get more information by calling the toll free number (888-NOW-NOVA (888-669-6682)) What are the ingredients in Estraderm? The Estraderm system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. Alcohol is also released from the system during use. REV: APRIL 2004 Printed in U.S.A. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © 2000 Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.377454	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19081slr036,039_estraderm_lbl.pdf', 'application_number': 19081, 'submission_type': 'SUPPL ', 'submission_number': 36}
11,436	Tussionex® Pennkinetic® (hydrocodone polistirex and chlorpheniramine polistirex) Extended-Release Suspension Rx only Rev. 01/2008 1E DESCRIPTION Each teaspoonful (5 mL) of TUSSIONEX Pennkinetic Extended-Release Suspension contains hydrocodone polistirex equivalent to 10 mg of hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 8 mg of chlorpheniramine maleate. TUSSIONEX Pennkinetic Extended- Release Suspension provides up to 12-hour relief per dose. Hydrocodone is a centrally-acting narcotic antitussive. Chlorpheniramine is an antihistamine. TUSSIONEX Pennkinetic Extended- Release Suspension is for oral use only. Hydrocodone Polistirex Sulfonated styrene-divinylbenzene copolymer complex with 4,5α-epoxy-3-methoxy-17- methylmorphinan-6-one. Hydrocodone Polistirex chemical structure Chlorpheniramine Polistirex Sulfonated styrene-divinylbenzene copolymer complex with 2-[p-chloro-α-[2- (dimethylamino)ethyl]-benzyl]pyridine. Chlorpheniramine Polistirex chemical structure This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inactive Ingredients Ascorbic acid, D&C Yellow No. 10, ethylcellulose, FD&C Yellow No. 6, flavor, high fructose corn syrup, methylparaben, polyethylene glycol 3350, polysorbate 80, pregelatinized starch, propylene glycol, propylparaben, purified water, sucrose, vegetable oil, xanthan gum. CLINICAL PHARMACOLOGY Hydrocodone is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of codeine. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act directly on the cough center. In excessive doses, hydrocodone, like other opium derivatives, will depress respiration. The effects of hydrocodone in therapeutic doses on the cardiovascular system are insignificant. Hydrocodone can produce miosis, euphoria, and physical and psychological dependence. Chlorpheniramine is an antihistamine drug (H1 receptor antagonist) that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa. Hydrocodone release from TUSSIONEX Pennkinetic Extended-Release Suspension is controlled by the Pennkinetic System, an extended-release drug delivery system, which combines an ion- exchange polymer matrix with a diffusion rate-limiting permeable coating. Chlorpheniramine release is prolonged by use of an ion-exchange polymer system. Following multiple dosing with TUSSIONEX Pennkinetic Extended-Release Suspension, hydrocodone mean (S.D.) peak plasma concentrations of 22.8 (5.9) ng/mL occurred at 3.4 hours. Chlorpheniramine mean (S.D.) peak plasma concentrations of 58.4 (14.7) ng/mL occurred at 6.3 hours following multiple dosing. Peak plasma levels obtained with an immediate-release syrup occurred at approximately 1.5 hours for hydrocodone and 2.8 hours for chlorpheniramine. The plasma half-lives of hydrocodone and chlorpheniramine have been reported to be approximately 4 and 16 hours, respectively. INDICATIONS AND USAGE TUSSIONEX Pennkinetic Extended-Release Suspension is indicated for relief of cough and upper respiratory symptoms associated with allergy or a cold in adults and children 6 years of age and older. CONTRAINDICATIONS TUSSIONEX Pennkinetic Extended-Release Suspension is contraindicated in patients with a known allergy or sensitivity to hydrocodone or chlorpheniramine. The use of TUSSIONEX Pennkinetic Extended-Release Suspension is contraindicated in children less than 6 years of age due to the risk of fatal respiratory depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS Respiratory Depression As with all narcotics, TUSSIONEX Pennkinetic Extended-Release Suspension produces dose- related respiratory depression by directly acting on brain stem respiratory centers. Hydrocodone affects the center that controls respiratory rhythm and may produce irregular and periodic breathing. Caution should be exercised when TUSSIONEX Pennkinetic Extended-Release Suspension is used postoperatively and in patients with pulmonary disease, or whenever ventilatory function is depressed. If respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride and other supportive measures when indicated (see OVERDOSAGE). Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions, which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Obstructive Bowel Disease Chronic use of narcotics may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder. Pediatric Use The use of TUSSIONEX Pennkinetic Extended-Release Suspension is contraindicated in children less than 6 years of age (see CONTRAINDICATIONS). In pediatric patients, as well as adults, the respiratory center is sensitive to the depressant action of narcotic cough suppressants in a dose-dependent manner. Caution should be exercised when administering TUSSIONEX Pennkinetic Extended-Release Suspension to pediatric patients 6 years of age and older. Overdose or concomitant administration of TUSSIONEX Pennkinetic Extended-Release Suspension with other respiratory depressants may increase the risk of respiratory depression in pediatric patients. Benefit to risk ratio should be carefully considered, especially in pediatric patients with respiratory embarrassment (e.g., croup) (see PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Caution is advised when prescribing this drug to patients with narrow-angle glaucoma, asthma, or prostatic hypertrophy. Special Risk Patients As with any narcotic agent, TUSSIONEX Pennkinetic Extended-Release Suspension should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Information for Patients As with all narcotics, TUSSIONEX Pennkinetic Extended-Release Suspension may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. TUSSIONEX Pennkinetic Extended-Release Suspension must not be diluted with fluids or mixed with other drugs as this may alter the resin-binding and change the absorption rate, possibly increasing the toxicity. Patients should be advised to measure TUSSIONEX Pennkinetic Extended-Release Suspension with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose. Shake well before using. Keep out of the reach of children. Cough Reflex Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when TUSSIONEX Pennkinetic Extended-Release Suspension is used postoperatively, and in patients with pulmonary disease. Drug Interactions Patients receiving narcotics, antihistaminics, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with TUSSIONEX Pennkinetic Extended-Release Suspension may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone. The concurrent use of other anticholinergics with hydrocodone may produce paralytic ileus. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with TUSSIONEX Pennkinetic Extended-Release Suspension. Pregnancy Teratogenic Effects – Pregnancy Category C Hydrocodone has been shown to be teratogenic in hamsters when given in doses 700 times the human dose. There are no adequate and well-controlled studies in pregnant women. TUSSIONEX Pennkinetic Extended-Release Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. Labor and Delivery As with all narcotics, administration of TUSSIONEX Pennkinetic Extended-Release Suspension to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TUSSIONEX Pennkinetic Extended-Release Suspension, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The use of TUSSIONEX Pennkinetic Extended-Release Suspension is contraindicated in children less than 6 years of age (see CONTRAINDICATIONS and ADVERSE REACTIONS, Respiratory, Thoracic and Mediastinal Disorders). TUSSIONEX Pennkinetic Extended-Release Suspension should be used with caution in pediatric patients 6 years of age and older (see WARNINGS, Pediatric Use). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of TUSSIONEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Gastrointestinal Disorders Nausea and vomiting may occur; they are more frequent in ambulatory than in recumbent patients. Prolonged administration of TUSSIONEX Pennkinetic Extended-Release Suspension may produce constipation. General Disorders and Administration Site Conditions Death Nervous System Disorders Sedation, drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, euphoria, dizziness, psychic dependence, mood changes. Renal and Urinary Disorders Ureteral spasm, spasm of vesical sphincters, and urinary retention have been reported with opiates. Respiratory, Thoracic and Mediastinal Disorders Dryness of the pharynx, occasional tightness of the chest, and respiratory depression (see CONTRAINDICATIONS). TUSSIONEX Pennkinetic Extended-Release Suspension may produce dose-related respiratory depression by acting directly on brain stem respiratory centers (see OVERDOSAGE). Use of TUSSIONEX Pennkinetic Extended-Release Suspension in children less than 6 years of age has been associated with fatal respiratory depression. Overdose with TUSSIONEX Pennkinetic Extended-Release Suspension in children 6 years of age and older, in adolescents, and in adults has been associated with fatal respiratory depression. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin and Subcutaneous Tissue Disorders Rash, pruritus. DRUG ABUSE AND DEPENDENCE TUSSIONEX Pennkinetic Extended-Release Suspension is a Schedule III narcotic. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of narcotics; therefore, TUSSIONEX Pennkinetic Extended-Release Suspension should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when TUSSIONEX Pennkinetic Extended-Release Suspension is used for a short time for the treatment of cough. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral narcotic use, although some mild degree of physical dependence may develop after a few days of narcotic therapy. OVERDOSAGE Signs and Symptoms Serious overdosage with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Although miosis is characteristic of narcotic overdose, mydriasis may occur in terminal narcosis or severe hypoxia. In severe overdosage apnea, circulatory collapse, cardiac arrest and death may occur. The manifestations of chlorpheniramine overdosage may vary from central nervous system depression to stimulation. Treatment Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote for respiratory depression which may result from overdosage or unusual sensitivity to narcotics including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of hydrocodone in this formulation may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory depression. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION It is important that TUSSIONEX is measured with an accurate measuring device (see PRECAUTIONS, Information for Patients). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Shake well before using. Adults and Children 12 Years and Older 5 mL (1 teaspoonful) every 12 hours; do not exceed 10 mL (2 teaspoonfuls) in 24 hours. Children 6-11Years of Age 2.5 mL (½ teaspoonful) every 12 hours; do not exceed 5 mL (1 teaspoonful) in 24 hours. This medicine is contraindicated in children under 6 years of age (see CONTRAINDICATIONS). HOW SUPPLIED TUSSIONEX Pennkinetic (hydrocodone polistirex and chlorpheniramine polistirex) Extended- Release Suspension is a gold-colored suspension. NDC 53014-548-67 473 mL bottle For Medical Information Contact: Medical Affairs Department Phone: (866) 822-0068 Fax: (770) 970-8859 Storage: Shake well. Dispense in a well-closed container. Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TUSSIONEX Pennkinetic Extended-Release Suspension Manufactured for: UCB, Inc. Smyrna, GA 30080 Logo TUSSIONEX and PENNKINETIC are trademarks of the UCB Group of companies. © 2008, UCB, Inc., Smyrna, GA 30080. All rights reserved. Printed in the U.S.A. Rev. 01/2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.428412	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019111s015lbl.pdf', 'application_number': 19111, 'submission_type': 'SUPPL ', 'submission_number': 15}
11,435	NDA 19-081/S-040 Page 3 Estraderm® estradiol transdermal system Continuous delivery for twice-weekly application Rx only Prescribing Information ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.) CARDIOVASCULAR AND OTHER RISKS Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular disorders and Dementia.) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50-79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies). The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated equine estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies). Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. DESCRIPTION Estraderm, estradiol transdermal system, is designed to release estradiol through a rate-limiting membrane continuously upon application to intact skin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 4 Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradiol per day via skin of average permeability (interindividual variation in skin permeability is approximately 20%). Each corresponding system having an active surface area of 10 or 20 cm2 contains 4 or 8 mg of estradiol USP and 0.3 or 0.6 mL of alcohol USP, respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5 (10)-triene-3,17ß- diol. The structural formula is HO H H H H CH3 OH The Estraderm system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. Alcohol is also released from the system during use. CLINICAL PHARMACOLOGY Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 5 In a study using transdermally administered estradiol, 0.1 mg daily, plasma levels increased by 66 pg/mL, resulting in an average plasma level of 73 pg/mL. There were no significant increases in the concentration of renin substrate or other hepatic proteins (sex hormone-binding globulin, thyroxine- binding globulin, and corticosteroid-binding globulin). Pharmacokinetics The skin metabolizes estradiol only to a small extent. In contrast, orally administered estradiol is rapidly metabolized by the liver to estrone and its conjugates, giving rise to higher circulating levels of estrone than estradiol. Therefore, transdermal administration produces therapeutic plasma levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Absorption Administration of Estraderm produces mean serum concentrations of estradiol comparable to those produced by daily oral administration of estradiol at about 20 times the daily transdermal dose. In single-application studies in 14 postmenopausal women using Estraderm systems that provided 0.05 and 0.1 mg of exogenous estradiol per day, these systems produced increased blood levels within 4 hours and maintained respective mean serum estradiol concentrations of 32 and 67 pg/mL above baseline over the application period. At the same time, increases in estrone serum concentration averaged only 9 and 27 pg/mL above baseline, respectively. Serum concentrations of estradiol and estrone returned to preapplication levels within 24 hours after removal of the system. The estimated daily urinary output of estradiol conjugates increased 5 to 10 times the baseline values and returned to near baseline within 2 days after removal of the system. By comparison, estradiol (2 mg/day) administered orally to postmenopausal women resulted in increases in mean serum concentration of 59 pg/mL of estradiol and 302 pg/mL of estrone above baseline on the third consecutive day of dosing. Urinary output of estradiol conjugates after oral administration increased to about 100 times the baseline values and did not approach baseline until 7-8 days after the last dose. In a 3-week multiple-application study of 14 postmenopausal women in which Estraderm 0.05 was applied twice weekly, the mean increments in steady-state serum concentration were 30 pg/mL for estradiol and 12 pg/mL for estrone. Urinary output of estradiol conjugates returned to baseline within 3 days after removal of the last (6th) system, indicating little or no estrogen accumulation in the body. Distribution No specific investigation of the tissue distribution of estradiol absorbed from Estraderm in humans has been conducted. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 6 sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Excretion Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Transdermal administration produces therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conjugates and requires smaller total doses than does oral therapy. Because estradiol has a short half-life (~1 hour), transdermal administration of estradiol allows a rapid decline in blood levels after an Estraderm system is removed, e.g., in a cycling regimen. Special Populations Estraderm was only investigated in postmenopausal women. Drug Interactions In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects. Clinical Studies Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of the use of 0.625 mg conjugated equine estrogens (CE) per day alone and of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 7 Table 1, RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHIa Placebo n= 8102 CE/MPA n= 8506 Eventc Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI) Absolute Risk per 10,000 woman-years CHD events Non-fatal MI CHD death 1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97) 30 23 6 37 30 7 Invasive breast cancerb 1.26 (1.00-1.59) 30 38 Stroke 1.41 (1.07-1.85) 21 29 Pulmonary embolism 2.13 (1.39-3.25) 8 16 Colorectal cancer 0.63 (0.43-0.92) 16 10 Endometrial cancer 0.83 (0.47-1.47) 6 5 Hip fracture 0.66 (0.45-0.98) 15 10 Death due to causes other than the events above 0.92 (0.74-1.14) 40 37 Global indexc 1.15 (1.03-1.28) 151 170 Deep vein thrombosisd 2.07 (1.49-2.87) 13 26 Vertebral fracturesd 0.66 (0.44-0.98) 15 9 Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131 a adapted from JAMA, 2002: 288: 321-333 b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer c a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. d not included in Global index nominal confidence intervals unadjusted for multiple looks and multiple comparisons For those outcomes included in the “global index”, absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,00 woman-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 8 was 19 per 10,000 woman-years. There was no difference between the groups in terms of all-cause mortality (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.) Women’s Health Initiative Memory Study The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 woman-years) and 21 in the placebo group (22 per 10,000 woman-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.) INDICATIONS AND USAGE Estraderm® (estradiol transdermal system) is indicated in: 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risks of osteoporosis and non-estrogen medications should be carefully considered. The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. CONTRAINDICATIONS Estrogens should not be used in individuals with any of the following conditions: 1. Undiagnosed abnormal genital bleeding. 2. Known, suspected or history of cancer of the breast. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 9 5. Active or recent (e.g. within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. Liver dysfunction or disease. 7. Estraderm® (estradiol transdermal system) should not be used in patients with known hypersensitivity to its ingredients. 8. Known or suspected pregnancy. There is no indication for Estraderm in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (see PRECAUTIONS.) WARNINGS See BOXED WARNINGS. The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. 1. Cardiovascular disorders Estrogen and estrogen/progestin therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a. Coronary heart disease and stroke In the Women’s Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years). The increase in risk was observed in year one and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 woman-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/ 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 10 CHD events were comparable among women in the CE/MPA group and in the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. b. Venous thromboembolism (VTE) In the Women’s Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Endometrial cancer The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. b. Breast cancer The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration. The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 11 was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01- 1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 woman-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 woman-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. 3. Dementia In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 woman-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 woman- years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.) 4. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. 5. Hypercalcemia Administration of estrogen may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 12 6. Visual abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer. 2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use. 3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. 4. Impaired liver function and past history of cholestatic jaundice. Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. 5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6. Fluid retention. Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. 7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia. 8. Ovarian cancer. The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 13 but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. 9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 10. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B. Patient Information. Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Estraderm. C. Laboratory Tests. Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH). D. Drug/Laboratory Test Interactions. 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL-2 HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 14 E. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.) Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. F. Pregnancy. Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS.) G. Nursing Mothers. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Estraderm is administered to a nursing woman. H. Pediatric Use. Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. (See INDICATIONS and DOSAGE AND ADMINISTRATION.) I. Geriatric Use. Clinical studies of Estraderm did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautions, usually starting at the low end of the range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 15 increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.) ADVERSE REACTIONS See BOXED WARNINGS, WARNINGS and PRECAUTIONS. The most commonly reported adverse reaction to Estraderm in clinical trials was redness and irritation at the application site. This occurred in about 17% of the women treated and caused approximately 2% to discontinue therapy. Reports of rash have been rare. There have also been rare reports of severe systemic allergic reactions. The following additional adverse reactions have been reported with estrogens: 1. Genitourinary system. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrheal, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer. 2. Breasts. Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer. 3. Cardiovascular. Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure. 4. Gastrointestinal. Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gall bladder disease; pancreatitis, enlargement of hepatic hemangiomas. 5. Skin. Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash. 6. Eyes. Retinal vascular thrombosis; intolerance to contact lenses. 7. Central nervous system. Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia. 8. Miscellaneous. Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 16 OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of estrogen- containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. DOSAGE AND ADMINISTRATION The adhesive side of the Estraderm system should be placed on a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). The site selected should be one that is not exposed to sunlight. Estraderm should not be applied to the breasts. The Estraderm system should be replaced twice weekly. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the system off. The system should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the unlikely event that a system should fall off, the same system may be reapplied. If necessary, a new system may be applied. In either case, the original treatment schedule should be continued. Initiation of Therapy When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen alone or in combination with a progestin, should be with the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g. 3-month to 6-month intervals) to determine whether treatment is still necessary (See BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Estraderm is currently available in two dosage forms – 0.05 mg and 0.1 mg. Patients should be started at the lowest dose. The lowest effective dose of Estraderm has not been determined. For treatment of moderate to severe vasomotor symptoms or moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause, initiate therapy with Estraderm 0.05 applied to the skin twice weekly. Prophylactic therapy with Estraderm to prevent postmenopausal bone loss should be initiated with the 0.05 mg/day dosage as soon as possible after menopause. The dosage may be adjusted if necessary. Discontinuation of estrogen therapy may reestablish bone loss at a rate comparable to the immediate postmenopausal period. In women not currently taking oral estrogens, treatment with Estraderm may be initiated at once. In women who are currently taking oral estrogen, treatment with Estraderm should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 17 Therapeutic Regimen Estraderm therapy may be given continuously in patients who do not have an intact uterus. In those patients with an intact uterus, Estraderm may be given on a cyclic schedule (e.g., 3 weeks on drug followed by 1 week off drug). HOW SUPPLIED Estraderm estradiol transdermal system 0.05 mg/day – each 10 cm2 system contains 4 mg of estradiol USP for nominal* delivery of 0.05 mg of estradiol per day. Patient Calendar Pack of 8 Systems ................................................NDC 0083-2310-08 Carton of 6 Patient Calendar Packs of 8 Systems ..........................NDC 0083-2310-62 Carton of 1 Patient Calendar Pack of 24 Systems............................NDC 0083-2310-24 Estraderm estradiol transdermal system 0.1 mg/day – each 20 cm2 system contains 8 mg of estradiol USP for nominal* delivery of 0.1 mg of estradiol per day. Patient Calendar Pack of 8 Systems................................................NDC 0083-2320-08 Carton of 6 Patient Calendar Packs of 8 Systems ...........................NDC 0083-2320-62 Carton of 1 Patient Calendar Pack of 24 Systems............................NDC 0083-2320-24 _____________________ *See DESCRIPTION. Do not store above 30°C (86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch. REV: JUNE 2004 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 18 PATIENT INFORMATION Estraderm® (estradiol transdermal system) Read this PATIENT INFORMATION before you start using Estraderm® (estradiol transdermal system) and read all the information that you get each time you refill Estraderm. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment. What is the most important information I should know about Estraderm (an estrogen hormone)? • Estrogens increase the chances of getting cancer of the uterus. Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause. • Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes. Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your health care provider should talk regularly about whether you still need treatment with Estraderm. What is Estraderm®? Estraderm is a patch that contains the estrogen hormone, estradiol. When applied to the skin as directed below, Estraderm releases estrogen through the skin into the bloodstream. What is Estraderm used for? Estraderm is used after menopause to: • reduce moderate to severe hot flashes. Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 19 will not need estrogens. In other women, symptoms can be more severe. You and your health care provider should talk regularly about whether you still need treatment with Estraderm. • treat moderate to severe dryness, itching and burning in or around the vagina . You and your health care provider should talk regularly about whether you still need treatment with Estraderm to control these problems. If you use Estraderm only to treat your dryness, itching, and burning in or around your vagina, talk with your health care provider about whether a topical vaginal product would be better for you. • treat certain conditions in which a young woman’s ovaries do not produce enough estrogens naturally. • help reduce your chances of getting osteoporosis (thin weak bones). Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estraderm only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrogens might be better for you. You and your health care provider should talk regularly about whether you should continue with Estraderm. Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your health care provider before starting them. Who should not use Estraderm? Do not start taking Estraderm if you: • have unusual vaginal bleeding. • currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take Estraderm. • had a stroke or heart attack in the recent past (for example in the past year). • currently have or have had blood clots. • currently have or have had liver problems. • are allergic to Estraderm or any of its ingredients. See the end of this leaflet for a list of ingredients in Estraderm. • think you may be, or know that you are, pregnant. Tell your health care provider: • if you are breastfeeding. The hormone in Estraderm can pass into your milk. • about all of your medical problems: Your health care provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 20 migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. • about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Estraderm works. Estraderm may also affect how other medicines work. • if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens. How should I use Estraderm? 1. Start at the lowest dose and talk to your health care provider about how well that dose is working for you. 2. Estrogens should be used at the lowest dose possible for your treatment, only as long as needed. The lowest effective dose of Estraderm has not been determined. You and your health care provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Estraderm. How and Where to Apply Estraderm Each Estraderm system is individually sealed in a protective pouch. Tear open this pouch at the indentation (do not use scissors) and remove the system. Bubbles in the system are normal. A stiff protective liner covers the adhesive side of the system — the side that will be placed against your skin. This liner must be removed before applying the system. Slide the protective liner sideways between your thumb and index finger. Then hold the system at one edge. Remove the protective liner and discard it. Try to avoid touching the adhesive. Apply the adhesive side of the system to a clean, dry area of the skin on the trunk of the body (including the buttocks and abdomen). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 21 The site selected should be one that is not exposed to sunlight. Some women may find that it is more comfortable to wear Estraderm on the buttocks. Do not apply Estraderm to your breasts. The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site. The area selected should not be oily, damaged, or irritated. Avoid the waistline, since tight clothing may rub the system off. Apply the system immediately after opening the pouch and removing the protective liner. Press the system firmly in place with the palm of your hand for about 10 seconds, making sure there is good contact, especially around the edges. The Estraderm system should be worn continuously until it is time to replace it with a new system. You may wish to experiment with different locations when applying a new system, to find ones that are most comfortable for you and where clothing will not rub on the system. When to Apply Estraderm The Estraderm system should be replaced twice weekly. Your Estraderm package contains a calendar checklist on the back to help you remember a schedule. Mark the 2-day schedule you plan to follow. Always change the system on the 2 days of the week you have marked. When changing the system, remove the used Estraderm and discard it. Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Estraderm on a different skin site. (The same skin site should not be used again for at least 1 week after removal of the system). Please note: Contact with water when you are bathing, swimming, or showering will not affect the system. In the unlikely event that a system should fall off, put this same system back on and continue to follow your original treatment schedule. If necessary, you may apply a new system but continue to follow your original schedule. What are the possible side effects of estrogens? Less common but serious side effects include: ---- Breast cancer ---- Cancer of the uterus ---- Stroke ---- Heart attack ---- Blood clots ---- Dementia ---- Gallbladder disease. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 22 ---- Ovarian cancer These are some of the warning signs of serious side effects: ---- Breast lumps. ---- Unusual vaginal bleeding. ---- Dizziness and faintness ---- Changes in speech ---- Severe headaches ---- Chest pain ---- Shortness of breath ---- Pains in your legs ---- Changes in vision ---- Vomiting Call your health care provider right away if you get any of these warning signs, or any other unusual symptom that concerns you Common side effects include: ---- Headache ---- Breast pain ---- Irregular vaginal bleeding or spotting ---- Stomach/abdominal cramps, bloating ---- Nausea and vomiting ---- Hair loss Other side effects include: ---- High blood pressure ---- Liver problems ---- High blood sugar ---- Fluid retention ---- Enlargement of benign tumors of the uterus (“fibroids”) ---- Vaginal yeast infection Other side effects of Estraderm may be possible. If you have questions, talk to your health care provider or pharmacist. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 23 What can I do to lower my chances of a serious side effect with Estraderm? • Talk with your health care provider regularly about whether you should continue taking Estraderm. • If you have a uterus, talk to your health care provider about whether the addition of a progestin is right for you. • See your health care provider right away if you get vaginal bleeding while taking Estraderm. • Have a breast exam and mammogram (breast X-ray) every year unless your health care provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. • If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your health care provider for ways to lower your chances for getting heart disease. General information about safe and effective use of Estraderm Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Estraderm for conditions for which it was not prescribed. Do not give Estraderm to other people, even if they have the same symptoms you have. It may harm them. Keep Estraderm out of the reach of children. This leaflet provides a summary of the most important information about Estraderm. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Estraderm that is written for health professionals. You can get more information by calling the toll free number (888-NOW-NOVA (888-669-6682)) What are the ingredients in Estraderm? The Estraderm system comprises four layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a transparent polyester/ethylene vinyl acetate copolymer film, (2) a drug reservoir of estradiol USP and alcohol USP gelled with hydroxypropyl cellulose NF, (3) an ethylene-vinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral oil NF and polyisobutylene. A protective liner (5) of siliconized polyester film is attached to the adhesive surface and must be removed before the system can be used. The active component of the system is estradiol. The remaining components of the system are pharmacologically inactive. Alcohol is also released from the system during use. REV:JUNE 2004 Printed in U.S.A. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-081/S-040 Page 24 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © 2004 Novartis This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.514513	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19081s040lbl.pdf', 'application_number': 19081, 'submission_type': 'SUPPL ', 'submission_number': 40}
11,440	ISOPTIN® SR (verapamil HCl) Sustained-Release Oral Tablets Rx only DESCRIPTION ISOPTIN® SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). ISOPTIN SR is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing 240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil hydrochloride, and as light violet, oval-shaped, film-coated tablets containing 120 mg verapamil hydrochloride.The tablets are designed for sustained-release of the drug in the gastrointestinal tract, sustained- release characteristics are not altered when the tablet is divided in half. structural formula C27H38N2O4•HCl............. M.W. 491.08 Benzeneacetronitrile, α [3-[[2-(3,4-dimethoxyphenyl) ethyl] methylamino] propyl]-3,4 dimethoxy-α-(1-methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not chemically related to other cardioactive drugs. In addition to verapamil HCl, the ISOPTIN SR tablet contains the following ingredients: alginate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and titanium dioxide. The following are the color additives per tablet strength: Strength (mg) Color Additive(s) 120 Iron Oxide 180 Iron Oxide 240 D&C yellow #10 Lake dye, and FD&C blue #2 Lake dye CLINICAL PHARMACOLOGY ISOPTIN (verapamil HCl) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Mechanism of Action Essential Hypertension ISOPTIN exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise ISOPTIN does not alter systolic cardiac function in patients with normal ventricular function. ISOPTIN does not 1 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of ISOPTIN. Other Pharmacological Actions of ISOPTIN Include the Following ISOPTIN (verapamil HCl) dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of ISOPTIN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. ISOPTIN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, ISOPTIN prolongs the effective refractory period within the AV node and slows AV conduction in a rate related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, ISOPTIN may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS). ISOPTIN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. ISOPTIN may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS). ISOPTIN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Pharmacokinetics and Metabolism: With the immediate release formulation, more than 90% of the orally administered dose of ISOPTIN is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of ISOPTIN every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. 2 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In multiple dose studies under fasting conditions the bioavailability measured by AUC of ISOPTIN SR was similar to ISOPTIN immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg ISOPTIN SR with food produced peak plasma verapamil concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/mL. When ISOPTIN SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to trough ratio. Good correlation of dose and response is not available, but controlled studies of ISOPTIN SR have shown effectiveness of doses similar to the effective doses of ISOPTIN (immediate release). In healthy man, orally administered ISOPTIN undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with onethird of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg•hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values. (See PRECAUTIONS: Drug Interactions.) Hemodynamics and Myocardial Metabolism: ISOPTIN reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with ISOPTIN therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of ISOPTIN is countered by reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mmHg or ejection fraction less than 30%), or in patients taking beta- adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see DRUG INTERACTIONS). 3 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pulmonary Function: ISOPTIN does not induce bronchoconstriction and hence, does not impair ventilatory function. INDICATIONS AND USAGE ISOPTIN SR (verapamil HCl) is indicated for the management of essential hypertension. CONTRAINDICATIONS Verapamil HCl is contraindicated in: 1. Severe left ventricular dysfunction (see WARNINGS) 2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). 5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS). 6. Patients with known hypersensitivity to verapamil hydrochloride. WARNINGS Heart Failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS). Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension. Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after 4 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN. Atrioventricular Block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCI and institution of appropriate therapy depending upon the clinical situation. Patients with Hypertrophic Cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mmHg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second- degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued. PRECAUTIONS General Use in Patients with Impaired Hepatic Functions: Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out. Use in Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. Use in Patients with Impaired Renal Function: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE). 5 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telethromycin, an antibiotic in the ketolide class of antibiotics. HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. Cytochrome inducers/inhibitors: In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g. erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g. rifampin) have caused a lowering of plasma levels of verapamil, therefore, patients should be monitored for drug interactions. Aspirin: In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding time greater than observed with aspirin alone. Grapefruit juice: The intake of grapefruit juice may increase drug levels of verapamil. Beta Blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when 6 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda verapamil is administered, and the patient should be carefully monitored to avoid over or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. Upon discontinuation of ISOPTIN (verapamil HCl), the patient should be reassessed to avoid underdigitalization. Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. Antiarrhythmic Agents Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide: A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Other Alcohol: Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithuim levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. 7 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carbamazepine: Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine. Theophylline: Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline. Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility: An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. 8 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric Use: Safety and efficacy of ISOPTIN tablets in pediatric patients below the age of 18 years have not been established. Animal Pharmacology and/or Animal Toxicology: In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man. ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients. Constipation 7.3% Fatigue 1.7% Dizziness 3.3% Dyspnea 1.4% Nausea 2.7% Bradycardia (HR < 50/min) 1.4% Hypotension 2.5% AV Block-total (1 °, 2 °, 3 °) 1.2% Headache 2.2% 2 ° and 3 ° 0.8% Edema 1.9% Rash 1.2% CHF/Pulmonary Edema 1.8% Flushing 0.6% Elevated Liver Enzymes (see WARNING) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship. Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and Lymphatic: ecchymosis or bruising. 9 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, parasthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. Skin: arthralgia and rash, exanthema, hair loss hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special Senses: blurred vision, tinnitus. Urogenital: gynecomastia, impotence, galactorrhea/ hyperprolactinemia, increased urination, spotty menstruation. Treatment of Acute Cardiovascular Adverse Reactions: The frequency of cardiovascular adverse reactions that require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, norepinephrine bitartrate, atropine sulfate (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours [especially ISOPTIN® SR (verapamil hydrochloride)] preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. In overdose, tablets of ISOPTIN SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. 10 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Essential Hypertension The dose of ISOPTIN SR should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, ISOPTIN SR, given in the morning. Lower, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of ISOPTIN SR are evident within the first week of therapy. If adequate response is not obtained with 180 mg of ISOPTIN SR, the dose may be titrated upward in the following manner: a) 240 mg each morning, b) 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening c) 240 mg every twelve hours. When switching from immediate release ISOPTIN to ISOPTIN SR, the total daily dose in milligrams may remain the same. HOW SUPPLIED ISOPTIN® SR 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side and “ST” on the other side. ISOPTIN® SR 180 mg tablets are supplied as light pink, oval shaped, scored, film-coated tablets containing 180 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side, and “SK” on the other side. The ISOPTIN® SR 120 mg tablets are supplied as light violet, oval shaped, film-coated tablets containing 120 mg of verapamil hydrochloride. The tablet is embossed with “p” on one side and “SC” on the other side. 240 mg (light green)- Bottle of 100-NDC # 10631-490-01 Bottle of 500- NDC # 10631-490-05 180 mg (light pink)- Bottle of 100- NDC # 10631-489-01 120 mg (light violet)- Bottle of 100- NDC # 10631-488-01 Storage: Store at 25 ° C (77 ° F); excursions permitted to 15 °–30 ° C (59 °– 86 ° F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Halo Pharmaceutical Inc. Whippany, NJ 07981, USA Manufactured for: Ranbaxy Laboratories Inc. Jacksonville, FL 32257 USA October 2011 11 Reference ID: 3052165 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.776727	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019152s035lbl.pdf', 'application_number': 19152, 'submission_type': 'SUPPL ', 'submission_number': 35}
11,437	Locoid® (hydrocortisone butyrate) Solution, 0.1% For topical use DESCRIPTION Locoid® (hydrocortisone butyrate) Solution, 0.1% contains the topical corticosteroid, hydrocortisone butyrate, a non-fluorinated hydrocortisone ester. It has the chemical name: 11β,17,21-Trihydroxypregn-4 ene-3,20-dione 17-butyrate; the molecular formula: C25H36O6; the molecular weight: 432.54; and the CAS registry number: 13609-67-1. Its structural formula is: structural formula Each mL of Locoid® Solution contains 1 mg of hydrocortisone butyrate in a vehicle consisting of isopropyl alcohol (50% v/v), glycerin, povidone, anhydrous citric acid, sodium citrate and purified water. CLINICAL PHARMACOLOGY Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. INDICATIONS AND USAGE Locoid® (hydrocortisone butyrate) Solution, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of seborrheic dermatitis. CONTRAINDICATIONS None. Reference ID: 3650056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent corticosteroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical corticosteroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of corticosteroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS – Pediatric Use). If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for Patients Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than that for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Carcinogenesis, Mutagenesis, Impairment of Fertility Note: The animal multiples of human exposure calculations in this label were based on body surface area comparisons for an adult (i.e., mg/m2/day dose comparisons) assuming 100% human percutaneous absorption of a maximum topical human dose (MTHD) for hydrocortisone butyrate solution (25 g). In a 2-year dermal rat carcinogenicity study with Locoid® Lotion, hydrocortisone butyrate was administered to Sprague-Dawley rats at topical doses of 0.05, 0.15, and 0.3 mg/kg/day in males and 0.1, 0.25, and 0.5 mg/kg/day in females (0.1% lotion). No drug-related tumors were noted in this study up to the highest doses evaluated in this study of 0.3 mg/kg/day in males (0.1X MTHD) and 0.5 mg/kg/day in females (0.2X MTHD). Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and L5178Y/TK+/- mouse lymphoma assay) and one in vivo genotoxicity test (mouse micronucleus assay). No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day (0.7X MTHD). Mild effects on maternal animals, such as reduced food consumption and a subsequent reduction in body weight gain, were seen at doses ≥0.6 mg/kg/day (0.2X MTHD). Reference ID: 3650056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Category C Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 0.6, 1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 6 – 17. In the presence of maternal toxicity, fetal effects noted at 5.4 mg/kg/day (2X MTHD) included an increased incidence of ossification variations and unossified sternebra. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at doses of 5.4 and 1.8 mg/kg/day, respectively (2X MTHD and 0.7X MTHD, respectively). Subcutaneous doses of 0.1, 0.2 and 0.3 mg/kg/day hydrocortisone butyrate were administered to pregnant female rabbits during gestation days 7 – 20. An increased incidence of abortion was noted at 0.3 mg/kg/day (0.2X MTHD). In the absence of maternal toxicity, a dose-dependent decrease in fetal body weight was noted at doses ≥0.1 mg/kg/day (0.1X MTHD). Additional indicators of embryofetal toxicity (reduction in litter size, decreased number of viable fetuses, increased post-implantation loss) were noted at doses ≥0.2 mg/kg/day (0.2X MTHD). Additional fetal effects noted in this study included delayed ossification noted at doses ≥0.1 mg/kg/day and an increased incidence of fetal malformations (primarily skeletal malformations) noted at doses ≥0.2 mg/kg/day. A dose at which no treatment-related effects on embryofetal toxicity or teratogenicity were observed was not established in this study. Additional systemic embryofetal development studies were conducted in rats and mice. Subcutaneous doses of 0.1 and 9 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 9 – 15. In the presence of maternal toxicity, an increase in fetal deaths and fetal resorptions and an increase in the number of ossifications in caudal vertebrae were noted at a dose of 9 mg/kg/day (3X MTHD). No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 0.1 mg/kg/day (0.1X MTHD). Subcutaneous doses of 0.2 and 1 mg/kg/day hydrocortisone butyrate were administered to pregnant female mice during gestation days 7 – 13. In the absence of maternal toxicity, an increased number of cervical ribs and one fetus with clubbed legs were noted at a dose of 1 mg/kg/day (0.2X MTHD). No treatment-related effects on embryofetal toxicity or teratogenicity were noted at doses of 1 and 0.2 mg/kg/day, respectively (0.2X MTHD and 0.1X MTHD, respectively). No topical embryofetal development studies were conducted with hydrocortisone butyrate solution. However, topical embryofetal development studies were conducted in rats and rabbits with a hydrocortisone butyrate ointment formulation. Topical doses of 1% and 10% hydrocortisone butyrate ointment were administered to pregnant female rats during gestation days 6 – 15 or pregnant female rabbits during gestation days 6 – 18. A dose-dependent increase in fetal resorptions was noted in rabbits (0.2 – 2X MTHD) and fetal resorptions were noted in rats at the 10% hydrocortisone butyrate ointment dose (80X MTHD). No treatment-related effects on embryofetal toxicity were noted at the 1% hydrocortisone butyrate ointment dose in rats (8X MTHD). A dose at which no treatment-related effects on embryofetal toxicity were observed in rabbits after topical administration of hydrocortisone butyrate ointment was not established in this study. No treatment-related effects on teratogenicity were noted at a dose of 10% hydrocortisone butyrate ointment in rats or rabbits (80X MTHD and 2X MTHD, respectively). A peri- and post-natal development study was conducted in rats. Subcutaneous doses of 0.6, 1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats from gestation day 6 – lactation day 20. In the presence of maternal toxicity, a dose-dependent decrease in fetal weight was noted at doses ≥1.8 mg/kg/day (0.7X MTHD). No treatment-related effects on fetal toxicity were noted at 0.6 mg/kg/day (0.2X MTHD). A delay in sexual maturation was noted at 5.4 mg/kg/day (2X MTHD). No treatment-related effects on sexual maturation were noted at 1.8 mg/kg/day. No treatment-related effects on behavioral development or subsequent reproductive performance were noted at 5.4 mg/kg/day. Reference ID: 3650056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to nursing women. Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. DOSAGE AND ADMINISTRATION Locoid® (hydrocortisone butyrate) Solution, 0.1% should be applied to the affected area as a thin film two or three times daily depending on the severity of the condition. HOW SUPPLIED Locoid® (hydrocortisone butyrate) Solution, 0.1% is supplied in polyethylene bottles containing: 60 mL (NDC 16781-391-60) STORAGE Store at controlled temperature between 5° to 25°C (41° to 77°F). Rx only Manufactured for: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA By: Ferndale Laboratories, Inc. Ferndale, MI 48220 Reference ID: 3650056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Locoid is a registered trademark of Astellas Pharma Europe B.V. under license. ©Valeant Pharmaceuticals International. 9422000 Revised: 10/2014 Reference ID: 3650056 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.816258	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019116s009lbl.pdf', 'application_number': 19116, 'submission_type': 'SUPPL ', 'submission_number': 9}
11,438	NDA 19-152/S-032 Page 3 ISOPTIN® SR (verapamil HCl) Sustained-Release Oral Tablets Rx only DESCRIPTION ISOPTIN® SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). ISOPTIN SR is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing 240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil hydrochloride, and as light violet, oval-shaped, film-coated tablets containing 120 mg verapamil hydrochloride.The tablets are designed for sustained-release of the drug in the gastrointestinal tract, sustained- release characteristics are not altered when the tablet is divided in half. Structural Formula C27H38N2O4•HCl............. M.W. 491.08 Benzeneacetronitrile, α [3-[[2-(3,4-dimethoxyphenyl) ethyl] methylamino] propyl]-3,4-dimethoxy-α (1-methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not chemically related to other cardioactive drugs. In addition to verapamil HCl, the ISOPTIN SR tablet contains the following ingredients: alginate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and titanium dioxide. The following are the color additives per tablet strength: Strength (mg) Color Additive(s) 120 Iron Oxide 180 Iron Oxide 240 D&C yellow #10 Lake dye, and FD&C blue #2 Lake dye CLINICAL PHARMACOLOGY ISOPTIN (verapamil HCl) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Mechanism of Action Essential Hypertension ISOPTIN exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise ISOPTIN does not alter systolic cardiac function in patients with normal ventricular function. ISOPTIN does not alter total serum calcium This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 4 levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of ISOPTIN. Other Pharmacological Actions of ISOPTIN Include the Following ISOPTIN (verapamil HCl) dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of ISOPTIN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate- pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. ISOPTIN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, ISOPTIN prolongs the effective refractory period within the AV node and slows AV conduction in a rate related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, ISOPTIN may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS). ISOPTIN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. ISOPTIN may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS). ISOPTIN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Pharmacokinetics and Metabolism: With the immediate release formulation, more than 90% of the orally administered dose of ISOPTIN is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of ISOPTIN every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 5 In multiple dose studies under fasting conditions the bioavailability measured by AUC of ISOPTIN SR was similar to ISOPTIN immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg ISOPTIN SR with food produced peak plasma verapamil concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/mL. When ISOPTIN SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to trough ratio. Good correlation of dose and response is not available, but controlled studies of ISOPTIN SR have shown effectiveness of doses similar to the effective doses of ISOPTIN (immediate release). In healthy man, orally administered ISOPTIN undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with onethird of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg•hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values. (See PRECAUTIONS: Drug Interactions.) Hemodynamics and Myocardial Metabolism: ISOPTIN reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with ISOPTIN therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of ISOPTIN is countered by reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mmHg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see DRUG INTERACTIONS). Pulmonary Function: ISOPTIN does not induce bronchoconstriction and hence, does not impair ventilatory function. INDICATIONS AND USAGE ISOPTIN SR (verapamil HCl) is indicated for the management of essential hypertension. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 6 CONTRAINDICATIONS Verapamil HCl is contraindicated in: 1. Severe left ventricular dysfunction (see WARNINGS) 2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). 5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson- White, Lown-Ganong-Levine syndromes). (see WARNINGS). 6. Patients with known hypersensitivity to verapamil hydrochloride. WARNINGS Heart Failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS). Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension. Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN. Atrioventricular Block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 7 especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCI and institution of appropriate therapy depending upon the clinical situation. Patients with Hypertrophic Cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mmHg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second- degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued. PRECAUTIONS General Use in Patients with Impaired Hepatic Functions: Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out. Use in Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. Use in Patients with Impaired Renal Function: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE). Drug Interactions Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Cytochrome inducers/inhibitors: In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g. erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g. rifampin) have caused a lowering of plasma levels of verapamil, therefore, patients should be monitored for drug interactions. Aspirin: In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding time greater than observed with aspirin alone. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 8 Grapefruit juice: The intake of grapefruit juice may increase drug levels of verapamil. Beta Blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. Upon discontinuation of ISOPTIN (verapamil HCl), the patient should be reassessed to avoid underdigitalization. Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. Antiarrhythmic Agents Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide: A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 9 Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Other Alcohol: Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithuim levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. Carbamazepine: Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine. Theophylline: Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline. Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility: An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 10 respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing Mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric Use: Safety and efficacy of ISOPTIN tablets in pediatric patients below the age of 18 years have not been established. Animal Pharmacology and/or Animal Toxicology: In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man. ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients. Constipation 7.3% Fatigue 1.7% Dizziness 3.3% Dyspnea 1.4% Nausea 2.7% Bradycardia (HR < 50/min) 1.4% Hypotension 2.5% AV Block-total (1 °, 2 °, 3 °) 1.2% Headache 2.2% 2 ° and 3 ° 0.8% Edema 1.9% Rash 1.2% CHF/Pulmonary Edema 1.8% Flushing 0.6% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 11 Elevated Liver Enzymes (see WARNING) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship. Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and Lymphatic: ecchymosis or bruising. Nervous System: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, parasthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. Skin: arthralgia and rash, exanthema, hair loss hyperkeratosis, maculae, sweating, urticaria, Stevens- Johnson syndrome, erythema multiforme. Special Senses: blurred vision, tinnitus. Urogenital: gynecomastia, impotence, galactorrhea/ hyperprolactinemia, increased urination, spotty menstruation. Treatment of Acute Cardiovascular Adverse Reactions: The frequency of cardiovascular adverse reactions that require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, norepinephrine bitartrate, atropine sulfate (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours [especially ISOPTIN® SR (verapamil hydrochloride)] preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. In overdose, tablets of ISOPTIN SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 12 might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. DOSAGE AND ADMINISTRATION Essential Hypertension The dose of ISOPTIN SR should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, ISOPTIN SR, given in the morning. Lower, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of ISOPTIN SR are evident within the first week of therapy. If adequate response is not obtained with 180 mg of ISOPTIN SR, the dose may be titrated upward in the following manner: a) 240 mg each morning, b) 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening c) 240 mg every twelve hours. When switching from immediate release ISOPTIN to ISOPTIN SR, the total daily dose in milligrams may remain the same. HOW SUPPLIED ISOPTIN® SR 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side and “ST” on the other side. ISOPTIN® SR 180 mg tablets are supplied as light pink, oval shaped, scored, film- coated tablets containing 180 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side, and “SK” on the other side. The ISOPTIN® SR 120 mg tablets are supplied as light violet, oval shaped, film-coated tablets containing 120 mg of verapamil hydrochloride. The tablet is embossed with “p” on one side and “SC” on the other side. 240 mg (light green)- Bottle of 100-NDC # 10631-490-01 Bottle of 500- NDC # 10631-490-05 180 mg (light pink)- Bottle of 100- NDC # 10631-489-01 120 mg (light violet)- Bottle of 100- NDC # 10631-488-01 Storage: Store at 25 ° C (77 ° F); excursions permitted to 15 °–30 ° C (59 °–86 ° F) [see USP Controlled Room Temperature]. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-152/S-032 Page 13 Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP. Manufactured by: Halo Pharmaceutical Inc. Whippany, NJ 07981, USA Manufactured for: Ranbaxy Laboratories Inc. Jacksonville, FL 32257 USA April, 2009 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.931429	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019152s032lbl.pdf', 'application_number': 19152, 'submission_type': 'SUPPL ', 'submission_number': 32}
11,439	NDA 19152/S-033 Page 3 Isoptin SR (verapamil HCl) Sustained-Release Oral Tablets Rx only DESCRIPTION Isoptin SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Isoptin SR is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing 240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil hydrochloride, and as light violet, oval-shaped, film-coated tablets containing 120 mg verapamil hydrochloride. The tablets are designed for sustained-release of the drug in the gastrointestinal tract, sustained- release characteristics are not altered when the tablet is divided in half. The structural formula of verapamil HCl is given below: Structural Formula C27H38N2O4•HCl............. M.W. 491.08 Benzeneacetronitrile, α [3-[[2-(3,4-dimethoxyphenyl) ethyl] methylamino] propyl]-3,4 dimethoxy-α-(1-methylethyl) hydrochloride Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not chemically related to other cardioactive drugs. In addition to verapamil HCl, the Isoptin SR tablet contains the following ingredients: alginate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and titanium dioxide. The following are the color additives per tablet strength: Strength (mg) Color Additive(s) 120 Iron Oxide 180 Iron Oxide 240 D&C yellow #10 Lake dye, and FD&C blue #2 Lake dye CLINICAL PHARMACOLOGY Isoptin (verapamil HCl) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 4 Mechanism of Action Essential Hypertension Isoptin exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise Isoptin does not alter systolic cardiac function in patients with normal ventricular function. Isoptin does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of Isoptin. Other Pharmacological Actions of Isoptin Include the Following Isoptin (verapamil HCl) dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of Isoptin in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Isoptin regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Isoptin prolongs the effective refractory period within the AV node and slows AV conduction in a rate related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, Isoptin may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS). Isoptin does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Isoptin may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS). Isoptin has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Pharmacokinetics and Metabolism: With the immediate release formulation, more than 90% of the orally administered dose of Isoptin is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 5 Chronic oral administration of 120 mg of Isoptin every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In multiple dose studies under fasting conditions the bioavailability measured by AUC of Isoptin SR was similar to Isoptin immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg Isoptin SR with food produced peak plasma verapamil concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/mL. When Isoptin SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to trough ratio. Good correlation of dose and response is not available, but controlled studies of Isoptin SR have shown effectiveness of doses similar to the effective doses of Isoptin (immediate release). In healthy man, orally administered Isoptin undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one- third of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 6 concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg•hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values (See PRECAUTIONS: Drug Interactions). Hemodynamics and Myocardial Metabolism: Isoptin reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with Isoptin therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of Isoptin is countered by reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mmHg or ejection fraction less than 30%), or in patients taking beta- adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see DRUG INTERACTIONS). Pulmonary Function: Isoptin does not induce bronchoconstriction and hence, does not impair ventilatory function. INDICATIONS AND USAGE Isoptin SR (verapamil HCl) is indicated for the management of essential hypertension. CONTRAINDICATIONS Verapamil HCl is contraindicated in: 1. Severe left ventricular dysfunction (see WARNINGS) 2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). 5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS). 6. Patients with known hypersensitivity to verapamil hydrochloride. WARNINGS Heart Failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 7 Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension. Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral Isoptin. Atrioventricular Block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCI and institution of appropriate therapy depending upon the clinical situation. Patients with Hypertrophic Cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mmHg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 8 PRECAUTIONS General Use in Patients with Impaired Hepatic Functions: Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out. Use in Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, prolongs recovery from the neuromuscular blocking agent vecuronium, and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. Use in Patients with Impaired Renal Function: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE). Drug Interactions Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telethromycin, an antibiotic in the ketolide class of antibiotics. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. Cytochrome inducers/inhibitors: In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil, therefore, patients should be monitored for drug interactions. Aspirin: In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding time greater than observed with aspirin alone. Grapefruit juice: The intake of grapefruit juice may increase drug levels of verapamil. Beta Blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and AV block, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 9 including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well- tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. Upon discontinuation of Isoptin (verapamil HCl), the patient should be reassessed to avoid underdigitalization. Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. Antiarrhythmic Agents Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide: A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 10 The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Other Alcohol: Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithuim levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. Carbamazepine: Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine. Theophylline: Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline. Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 11 Carcinogenesis, Mutagenesis, Impairment of Fertility: An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing Mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric Use: Safety and efficacy of Isoptin tablets in pediatric patients below the age of 18 years have not been established. Animal Pharmacology and/or Animal Toxicology: In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 12 ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients. Constipation 7.3% Fatigue 1.7% Dizziness 3.3% Dyspnea 1.4% Nausea 2.7% Bradycardia (HR < 50/min) 1.4% Hypotension 2.5% AV Block-total (1 °, 2 °, 3 °) 1.2% Headache 2.2% 2 ° and 3 ° 0.8% Edema 1.9% Rash 1.2% CHF/Pulmonary Edema 1.8% Flushing 0.6% Elevated Liver Enzymes (see WARNING) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship. Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and Lymphatic: ecchymosis or bruising. Nervous System: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, parasthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 13 Skin: arthralgia and rash, exanthema, hair loss hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special Senses: blurred vision, tinnitus. Urogenital: gynecomastia, impotence, galactorrhea/ hyperprolactinemia, increased urination, spotty menstruation. Treatment of Acute Cardiovascular Adverse Reactions: The frequency of cardiovascular adverse reactions that require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, norepinephrine bitartrate, atropine sulfate (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours [especially Isoptin SR (verapamil hydrochloride)] preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. In overdose, tablets of Isoptin SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19152/S-033 Page 14 agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. DOSAGE AND ADMINISTRATION Essential Hypertension The dose of Isoptin SR should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, Isoptin SR, given in the morning. Lower, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24-hours after the previous dose. The antihypertensive effects of Isoptin SR are evident within the first week of therapy. If adequate response is not obtained with 180 mg of Isoptin SR, the dose may be titrated upward in the following manner: a) 240 mg each morning, b) 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening c) 240 mg every twelve hours. When switching from immediate release Isoptin to Isoptin SR, the total daily dose in milligrams may remain the same. HOW SUPPLIED Isoptin SR 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side and “ST” on the other side. Isoptin SR 180 mg tablets are supplied as light pink, oval shaped, scored, film-coated tablets containing 180 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side, and “SK” on the other side. The Isoptin SR 120 mg tablets are supplied as light violet, oval shaped, film-coated tablets containing 120 mg of verapamil hydrochloride. The tablet is embossed with “p” on one side and “SC” on the other side. 240 mg (light green)- Bottle of 100-NDC # 10631-490-01 Bottle of 500- NDC # 10631-490-05 180 mg (light pink)- Bottle of 100- NDC # 10631-489-01 120 mg (light violet)- Bottle of 100- NDC # 10631-488-01 Storage: Store at 25 ° C (77 ° F); excursions permitted to 15 °–30 ° C (59 °–86 ° F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP. You may report side effects to FDA at 1-800-FDA-1088. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:15.934538	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019152s033lbl.pdf', 'application_number': 19152, 'submission_type': 'SUPPL ', 'submission_number': 33}
11,444	DESCRIPTION CARAFATE Suspension contains sucralfate and sucralfate is an a-D-glucopyranoside, ß-D- fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex. CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL. CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer. CLINICAL PHARMACOLOGY Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine. Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1. Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site. 2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions. 3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%. 4. In vitro, sucralfate adsorbs bile salts. These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1-g dose of sucralfate. CLINICAL TRIALS In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage regiment of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer healing. Results From Clinical Trials Healing Rates for Acute Duodenal Ulcer Treatment n Week 2 Healing Rates Week 4 Healing Rates Week 8 Healing Rates CARAFATE Suspension 145 23(16%)* 66(46%)† 95(66%)‡ Placebo 147 10(7%) 39(27%) 58(39%) *P=0.016 †P=0.001 ‡P=0.0001 Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE CARAFATE (sucralfate) Suspension is indicated in the short-term (up to 8 weeks) treatment of active duodenal ulcer. CONTRAINDICATIONS There are no known contraindications to the use of sucralfate. PRECAUTIONS Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the posthealing frequency or severity of duodenal ulceration. Special Populations: Chronic Renal Failure and Dialysis Patients When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure. Drug Interactions Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy. The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Because of the potential of CARAFATE to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose). There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted. Pregnancy Teratogenic effects. Pregnancy Category B. Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See DOSAGE AND ADMINISTRATION) This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. (See PRECAUTIONS Special Populations: Chronic Renal Failure and Dialysis Patients) Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate, adverse effects were reported in 129 (4.7%). Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system: Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea, vomiting Dermatological: pruritus, rash This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nervous System: dizziness, insomnia, sleepiness, vertigo Other: back pain, headache Postmarketing reports of hypersensitivity reactions, including urticaria (hives), angioedema, respiratory difficulty, rhinitis, laryngospasm, and facial swelling have been reported in patients receiving sucralfate tablets. Similar events were reported with sucralfate suspension. However, a causal relationship has not been established. Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings. Inadvertent injection of insoluble sucralfate and its insoluble excipients has led to fatal complications, including pulmonary and cerebral emboli. Sucralfate is not intended for intravenous administration. OVERDOSAGE Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given. Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting. DOSAGE AND ADMINISTRATION Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoonfuls) four times per day. CARAFATE should be administered on an empty stomach. Antacids may be prescribed as needed for relief of pain but should not be taken within one- half hour before or after sucralfate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination. Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See PRECAUTIONS Geriatric Use) HOW SUPPLIED CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 58914-170-14). SHAKE WELL BEFORE USING. Store at controlled room temperature 20-25°C (68-77°F)[see USP]. Avoid Freezing. Rx Only Prescribing Information as of April 2004 Axcan Scandipharm Inc. 22 Inverness Center Parkway Birmingham, AL 35242 www.axcan.com This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.144484	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019183s011lbl.pdf', 'application_number': 19183, 'submission_type': 'SUPPL ', 'submission_number': 11}
11,442	NDA 19-155/S-022 Page 3 Lac-Hydrin® (ammonium lactate) Lotion, 12% For Dermatologic use only. Not for Ophthalmic, Oral or Intravaginal use. DESCRIPTION Lac-Hydrin specially formulates 12% lactic acid, neutralized with ammonium hydroxide, as ammonium lactate to provide a lotion pH of 4.5-5.5. Lac-Hydrin (ammonium lactate) Lotion, 12% also contains cetyl alcohol, fragrance, glycerin, glyceryl stearate, laureth-4, light mineral oil, magnesium aluminum silicate, methylcellulose, methyl- and propylparabens, PEG-100 stearate, polyoxyl 40 stearate, propylene glycol and water. Lactic acid is a racemic mixture of 2-hydroxypropanoic acid and has the following structural formula: COOH CHOH CH3 CLINICAL PHARMACOLOGY Lactic acid is an alpha-hydroxy acid. It is a normal constituent of tissues and blood. The alpha-hydroxy acids (and their salts) may act as humectants when applied to the skin. This property may influence hydration of the stratum corneum. In addition, lactic acid, when applied to the skin, may act to decrease corneocyte cohesion. The mechanism(s) by which this is accomplished is not yet known. An in vitro study of percutaneous absorption of Lac-Hydrin Lotion using human cadaver skin indicates that approximately 5.8% of the material was absorbed after 68 hours. INDICATIONS AND USAGE Lac-Hydrin is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris and for temporary relief of itching associated with these conditions. CONTRAINDICATIONS Lac-Hydrin Lotion is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-155/S-022 Page 4 WARNINGS Sun exposure to areas of the skin treated with Lac-Hydrin (ammonium lactate) Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Lac-Hydrin Lotion should be discontinued if hypersensitivity is observed. PRECAUTIONS General For external use only. Stinging or burning may occur when applied to skin with fissures, erosions or that is otherwise abraded (for example, after shaving the legs). Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied. Information for Patients Patients using Lac-Hydrin (ammonium lactate) Lotion, 12% should receive the following information and instructions: 1. This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes. 2. Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin. 3. This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs). 4. If the skin condition worsens with treatment, the medication should be promptly discontinued. Carcinogenesis, Mutagenesis, Impairment of Fertility The topical treatment of CD-1 mice with 12%, 21% or 30% ammonium lactate formulations for two years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% ammonium lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation. The mutagenic potential of ammonium lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-155/S-022 Page 5 In dermal Segment I and III studies with ammonium lactate formulations there were no effects observed in fertility or pre- or post-natal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m2/day), approximately 0.4 times the human topical dose. Pregnancy Teratogenic Effects: Pregnancy Category B Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively (600 mg/kg/day, corresponding to 3600 mg/m2/day in the rat and 7200 mg/m2/day in the rabbit) and have revealed no evidence of impaired fertility or harm to the fetus due to ammonium lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Lac-Hydrin Lotion should be used during pregnancy only if clearly needed. Nursing Mothers Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lac-Hydrin is administered to a nursing woman. Pediatric Use Safety and effectiveness of Lac-Hydrin have been demonstrated in infants and children. No unusual toxic effects were reported. Geriatric Use Clinical studies of Lac-Hydrin (ammonium lactate) Lotion, 12% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious. ADVERSE REACTIONS The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-155/S-022 Page 6 OVERDOSAGE The oral administration of Lac-Hydrin to rats and mice showed this drug to be practically non-toxic (LD50 >15 mL/kg). DOSAGE AND ADMINISTRATION Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician. HOW SUPPLIED Lac-Hydrin® (ammonium lactate) Lotion, 12% is available in a 225g (NDC 0072-5712-08) plastic bottle and a 400g (NDC 0072-5712-14) plastic bottle. Store at controlled room temperature 15° C-30° C (59° F-86° F). Manufactured for: Bristol-Myers Squibb Co. Princeton, NJ 08543 USA by: Contract Pharmaceuticals Limited Niagara Buffalo, NY 14213 USA [Print Code TBD] [Rev Date TBD] This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.164485	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019155s022lbl.pdf', 'application_number': 19155, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,446	CARAFATE® (sucralfate) Suspension DESCRIPTION CARAFATE Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex. st ruc tur al fo rm ula [Al(OH)3] x [H2O]y (x=8 to 10 and y= 22 to 31) R= SO3Al(OH)2 CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL. CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer. CLINICAL PHARMACOLOGY Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine. Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent: 1. Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site. 2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions. 3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%. In vitro, sucralfate adsorbs bile salts. These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1 g dose of sucralfate. CLINICAL TRIALS In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage regimen of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer healing. Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Results from Clinical Trials Healing Rates for Acute Duodenal Ulcer Treatment n Week 2 Healing Rates Week 4 Healing Rates Week 8 Healing Rates CARAFATE Suspension 145 23(16%)* 66(46%)† 95(66%)‡ Placebo 147 10(7%) 39(27%) 58(39%) P=0.016 †P=0.001 ‡P=0.0001 Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated. INDICATIONS AND USAGE CARAFATE (sucralfate) Suspension is indicated in the short-term (up to 8 weeks) treatment of active duodenal ulcer. CONTRAINDICATIONS Carafate is contraindicated for patients with known hypersensitivity reactions to the active substance or to any of the excipients. PRECAUTIONS The physician should read the "PRECAUTIONS" section when considering the use of Carafate in pregnant or pediatric patients, or patients of childbearing potential. Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the post healing frequency or severity of duodenal ulceration. Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the anti- diabetic treatment dose during the use of sucralfate suspension might be necessary. Special Populations: Chronic Renal Failure and Dialysis Patients When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure. Drug Interactions Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy. The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda concomitant medication 2 hours before sucralfate eliminated the interaction. Due to CARAFATE`s potential to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose). There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted. Pregnancy Teratogenic effects. Pregnancy Category B. Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See DOSAGE AND ADMINISTRATION). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function (See PRECAUTIONS Special Populations: Chronic Renal Failure and Dialysis Patients). Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate, adverse effects were reported in 129 (4.7%). Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system: Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea, vomiting Dermatological: pruritus, rash Nervous System: dizziness, insomnia, sleepiness, vertigo Other: back pain, headache Post-marketing cases of hypersensitivity have been reported with the use of sucralfate suspension, including anaphylactic reactions, dyspnea, lip swelling, edema of the mouth, pharyngeal edema, pruritus, rash, swelling of the face and urticaria. Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cases of bronchospasm, laryngeal edema and respiratory tract edema have been reported with an unknown oral formulation of sucralfate. Cases of hyperglycemia have been reported with sucralfate. Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings. Inadvertent injection of insoluble complications, including pulmonary intravenous administration. sucralfate and cer and ebral its insoluble emboli. Su excipients cralfate is has led not inten to ded fatal for OVERDOSAGE Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given. Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting. DOSAGE AND ADMINISTRATION Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoons) four times per day. CARAFATE should be administered on an empty stomach. Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate. While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination. Elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See PRECAUTIONS Geriatric Use). Call your doctor for medical advice about side effects. You may report side effects to Aptalis Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch HOW SUPPLIED CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 58914-170-14). SHAKE WELL BEFORE USING. AVOID FREEZING. Store at controlled room temperature 20-25°C (68-77°F)[see USP]. Rx Only Prescribing Information rev. March 2013 Aptalis Pharma US, Inc. 100 Somerset Corporate Boulevard Bridgewater, NJ 08807 USA CARAFATE® is a registered trademark of Aptalis Pharma Canada Inc., which is an affiliate of Aptalis Pharma US, Inc. www.aptalispharma.com Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARAFATE® (sucralfate) Tablets U.S. Package Insert CARAFATE® Tablets (sucralfate) DESCRIPTION CARAFATE Tablets contain sucralfate and sucralfate is an α-D-glucopyranoside, β-D fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex. st ruc tur al fo rm ula [Al(OH)3] x [H2O]y (x=8 to 10 and y= 22 to 31) R= SO3Al(OH)2 Tablets for oral administration contain 1 g of sucralfate. Also contain: D & C Red #30 Lake, FD&C Blue #1 Lake, magnesium stearate, microcrystalline cellulose, and starch. Therapeutic category: antiulcer. CLINICAL PHARMACOLOGY Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine. Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent: 1. Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site. 2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions. 3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%. 4. In vitro, sucralfate adsorbs bile salts. These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1 g dose of sucralfate. CLINICAL TRIALS Acute Duodenal Ulcer Over 600 patients have participated in well-controlled clinical trials worldwide. Multicenter trials conducted in the United States, both of them placebo-controlled studies with endoscopic evaluation at 2 and 4 weeks, showed: 1 Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARAFATE® (sucralfate) Tablets U.S. Package Insert STUDY 1 Treatment Groups Ulcer Healing/ No. Patients 2 wk 4 wk (Overall) Sucralfate Placebo 37/105 (35.2%) 26/106 (24.5%) 82/109 (75.2%) 68/107 (63.6%) STUDY 2 Treatment Groups Ulcer Healing/ No. Patients 2 wk 4 wk (Overall) Sucralfate Placebo 8/24 (33%) 4/31 (13%) 22/24 (92%) 18/31 (58%) The sucralfate-placebo differences were statistically significant in both studies at 4 weeks but not at 2 weeks. The poorer result in the first study may have occurred because sucralfate was given 2 hours after meals and at bedtime rather than 1 hour before meals and at bedtime, the regimen used in international studies and in the second United States study. In addition, in the first study liquid antacid was utilized as needed, whereas in the second study antacid tablets were used. Maintenance Therapy After Healing of Duodenal Ulcer Two double-blind randomized placebo-controlled U.S. multicenter trials have demonstrated that sucralfate (1 g bid) is effective as maintenance therapy following healing of duodenal ulcers. In one study, endoscopies were performed monthly for 4 months. Of the 254 patients who enrolled, 239 were analyzed in the intention-to-treat life table analysis presented below. Duodenal Ulcer Recurrence Rate (%) Drug Months of Therapy n 1 2 3 4 CARAFATE Placebo 122 117 20 33 30* 46 38† 55 42† 63 P<0.05, †P<0.01 In this study, prn antacids were not permitted. In the other study, scheduled endoscopies were performed at 6 and 12 months, but for-cause endoscopies were permitted as symptoms dictated. Median symptom scores between the sucralfate and placebo groups were not significantly different. A life table intention-to-treat analysis for the 94 patients enrolled in the trial had the following results: Duodenal Ulcer Recurrence Rate (%) Drug n 6 months 12 months CARAFATE 48 19 27* Placebo 46 54 65 *P<0.002 In this study, prn antacids were permitted. Data from placebo-controlled studies longer than 1 year are not available. INDICATIONS AND USAGE CARAFATE® (sucralfate) is indicated in:  Short-term treatment (up to 8 weeks) of active duodenal ulcer. While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination. 2 Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARAFATE® (sucralfate) Tablets U.S. Package Insert  Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers. CONTRAINDICATIONS Carafate is contraindicated in patients with known hypersensitivity reactions to the active substance or to any of the excipients. PRECAUTIONS The physician should read the "PRECAUTIONS" section when considering the use of this drug in pregnant or pediatric patients, or patients of childbearing potential. Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the post healing frequency or severity of duodenal ulceration. Isolated reports of sucralfate tablet aspiration with accompanying respiratory complications have been received. Therefore, sucralfate tablets should be used with caution by patients who have known conditions that may impair swallowing, such as recent or prolonged intubation, tracheostomy, prior history of aspiration, dysphagia, or any other conditions that may alter gag and cough reflexes, or diminish oropharyngeal coordination or motility. Special Populations: Chronic Renal Failure and Dialysis Patients When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure. Drug Interactions Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy. The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all case studies to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Because of the potential of CARAFATE to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose). There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted. 3 Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARAFATE® (sucralfate) Tablets U.S. Package Insert Pregnancy Teratogenic effects. Pregnancy Category B. Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CARAFATE (sucralfate) Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See DOSAGE AND ADMINISTRATION). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function (See PRECAUTIONS Special Populations: Chronic Renal Failure and Dialysis Patients). Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Adverse reactions to sucralfate in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate tablets, adverse effects were reported in 129 (4.7%). Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system: Gastrointestinal: diarrhea, nausea, vomiting, gastric discomfort, indigestion, flatulence, dry mouth Dermatological: pruritus, rash Nervous System: dizziness, insomnia, sleepiness, vertigo Other: back pain, headache Post-marketing cases of hypersensitivity have been reported with the use of sucralfate tablets, including dyspnea, lip swelling, pruritus, rash, and urticaria. Cases of anaphylactic reactions, bronchospasm, laryngeal edema, edema of the mouth, pharyngeal edema, respiratory tract edema and swelling of the face have been reported with an unknown oral formulation of sucralfate. Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings. Inadvertent injection of insoluble sucralfate and its insolu complications, including pulmonary and cerebral emboli. intravenous administration. ble Su excipients cralfate is has not led inten to ded fatal for OVERDOSAGE 4 Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARAFATE® (sucralfate) Tablets U.S. Package Insert Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given. Acute oral toxicity studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting. DOSAGE AND ADMINISTRATION Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g four times per day on an empty stomach. Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate. While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination. Maintenance Therapy: The recommended adult oral dosage is 1 g twice a day. Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See PRECAUTIONS Geriatric Use). Call your doctor for medical advice about side effects. You may report side effects to Aptalis Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. HOW SUPPLIED CARAFATE (sucralfate) 1g tablets are supplied in bottles of 100 (NDC 58914-171-10). Light pink, scored, oblong tablets are embossed with CARAFATE on one side and 1712 on the other. Rx Only Prescribing Information rev March 2013 Aptalis Pharma US, Inc. 100 Somerset Corporate Boulevard Bridgewater, NJ 08807 CARAFATE® is a registered trademark of Aptalis Pharma Canada Inc., which is an affiliate of Aptalis Pharma US, Inc. www.aptalispharma.com 5 Reference ID: 3270329 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.377877	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018333s034,019183s016lbl.pdf', 'application_number': 19183, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,445	CARAFATE® (sucralfate) Suspension DESCRIPTION CARAFATE Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex. st ruc tur al fo rm ula CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL. CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer. CLINICAL PHARMACOLOGY Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine. Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent: 1. Studies in human subjects and with animal models of ulcer disease have shown that sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site. 2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions. 3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin activity in gastric juice by 32%. 4. In vitro, sucralfate adsorbs bile salts. These observations suggest that sucralfate’s antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1 g dose of sucralfate. CLINICAL TRIALS In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage regiment of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer healing. Reference ID: 2881256 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Results From Clinical Trials Healing Rates for Acute Duodenal Ulcer Treatment n Week 2 Healing Rates Week 4 Healing Rates Week 8 Healing Rates CARAFATE Suspension 145 23(16%)* 66(46%)† 95(66%)‡ Placebo 147 10(7%) 39(27%) 58(39%) *P=0.016 †P=0.001 ‡P=0.0001 Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated. INDICATIONS AND USAGE CARAFATE (sucralfate) Suspension is indicated in the short-term (up to 8 weeks) treatment of active duodenal ulcer. CONTRAINDICATIONS There are no known contraindications to the use of sucralfate. PRECAUTIONS Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can result in complete healing of the ulcer, a successful course of treatment with sucralfate should not be expected to alter the posthealing frequency or severity of duodenal ulceration. Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the anti diabetic treatment dose during the use of sucralfate suspension might be necessary. Special Populations: Chronic Renal Failure and Dialysis Patients When sucralfate is administered orally, small amounts of aluminum are absorbed from the gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum, such as aluminum-containing antacids, may increase the total body burden of aluminum. Patients with normal renal function receiving the recommended doses of sucralfate and aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients with renal impairment. Sucralfate should be used with caution in patients with chronic renal failure. Drug Interactions Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports. However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy. The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction. Because of the potential of CARAFATE to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical. In these cases, patients should be monitored appropriately. Reference ID: 2881256 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up to 1 g/kg (12 times the human dose). There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to 38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity studies were not conducted. Pregnancy Teratogenic effects. Pregnancy Category B. Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See DOSAGE AND ADMINISTRATION) This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. (See PRECAUTIONS Special Populations: Chronic Renal Failure and Dialysis Patients) Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate, adverse effects were reported in 129 (4.7%). Constipation was the most frequent complaint (2%). Other adverse effects reported in less than 0.5% of the patients are listed below by body system: Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea, vomiting Dermatological: pruritus, rash Nervous System: dizziness, insomnia, sleepiness, vertigo Other: back pain, headache Postmarketing reports of hypersensitivity reactions, including urticaria (hives), angioedema, respiratory difficulty, rhinitis, laryngospasm, and facial swelling have been reported in patients receiving sucralfate tablets. Similar events were reported with sucralfate suspension. However, a causal relationship has not been established. Cases of hyperglycemia have been reported with sucralfate. Bezoars have been reported in patients treated with sucralfate. The majority of patients had underlying medical conditions that may predispose to bezoar formation (such as delayed gastric emptying) or were receiving concomitant enteral tube feedings. Reference ID: 2881256 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Inadvertent injection of insoluble complications, including pulmonary intravenous administration. sucralfate and cer and ebral its insoluble emboli. Su excipients cralfate is has led not inten to ded fatal for OVERDOSAGE Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given. Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting. DOSAGE AND ADMINISTRATION Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoonfuls) four times per day. CARAFATE should be administered on an empty stomach. Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate. While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination. Elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See PRECAUTIONS Geriatric Use) Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. HOW SUPPLIED CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 58914-170-14). SHAKE WELL BEFORE USING. AVOID FREEZING. Store at controlled room temperature 20-25°C (68-77°F)[see USP]. Rx Only Prescribing Information as of December 2010 Axcan Pharma US, Inc. 22 Inverness Center Parkway Birmingham, AL 35242 USA www.axcan.com Reference ID: 2881256 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.425193	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019183s014lbl.pdf', 'application_number': 19183, 'submission_type': 'SUPPL ', 'submission_number': 14}
11,443	NDA 19-157/S-018 Page 1 Prednisolone Sodium Phosphate, USP, Oral Solution 6.7 mg / 5 mL Rx Only R539A Rev. 5/04 DESCRIPTION: Prednisolone sodium phosphate, USP, oral solution is a dye free, colorless to light straw colored, raspberry flavored solution. Each 5 mL (teaspoonful) contains 6.7 mg prednisolone sodium phosphate (5 mg prednisolone base) in a palatable, aqueous vehicle. Prednisolone sodium phosphate, USP, oral solution also contains dibasic sodium phosphate, edetate disodium, methylparaben, purified water, sodium biphosphate, sorbitol, natural and artificial raspberry flavor. Prednisolone sodium phosphate occurs as white or slightly yellow, friable granules or powder. It is freely soluble in water; soluble in methanol; slightly soluble in alcohol and in chloroform; and very slightly soluble in acetone and in dioxane. The chemical name of prednisolone sodium phosphate is pregna-1,4-diene-3,20-dione,11,17-dihydroxy-21-(phosphonooxy)-,disodium salt,(11β)-. The empirical formula is C21H27Na2O8P; the molecular weight is 484.39. Its chemical structure is: Pharmacological Category: Glucocorticoid CLINICAL PHARMACOLOGY: Naturally occurring glucocorticoids (hydrocortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Prednisolone is a synthetic adrenocortical steroid drug with predominantly glucocorticoid properties. Some of these properties reproduce the physiological actions of endogenous glucocorticosteroids, but others do not necessarily reflect any of the adrenal hormones’ normal functions; they are seen only after administration of large therapeutic doses of the drug. The pharmacological effects of prednisolone which are due to its glucocorticoid properties include: promotion of gluconeogenesis; increased deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; increased glomerular filtration rate and resulting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 2 increase in urinary excretion of urate (creatinine excretion remains unchanged); and increased calcium excretion. Depressed production of eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited. Prednisolone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisolone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension. Prednisolone is rapidly and well absorbed from the gastrointestinal tract following oral administration. Prednisolone sodium phosphate, USP, oral solution produces a 14% higher peak plasma level of prednisolone which occurs 20% faster than that seen with tablets. Prednisolone is 70-90% protein-bound in the plasma and it is eliminated from the plasma with a half-life of 2 to 4 hours. It is metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The systemic availability, metabolism and elimination of prednisolone after administration of single weight-based doses (0.8 mg/kg) of intravenous (IV) prednisolone and oral prednisone were reported in a small study of 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. Results showed that the systemic availability of total and unbound prednisolone, as well as interconversion between prednisolone and prednisone were independent of age. The mean unbound fraction of prednisolone was higher, and the steady-state volume of distribution (Vss) of unbound prednisolone was reduced in elderly patients. Plasma prednisolone concentrations were higher in elderly subjects, and the higher AUCs of total and unbound prednisolone were most likely reflective of an impaired metabolic clearance, evidenced by reduced fractional urinary clearance of 6β-hydroxyprednisolone. Despite these findings of higher total and unbound prednisolone concentrations, elderly subjects had higher AUCs of cortisol, suggesting that the elderly population is less sensitive to suppression of endogenous cortisol or their capacity for hepatic inactivation of cortisol is diminished. INDICATIONS AND USAGE: Prednisolone sodium phosphate, USP, oral solution is indicated in the following conditions: 1. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in adult and pediatric populations with: seasonal or perennial allergic rhinitis; asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions. 2. Dermatologic Diseases This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 3 Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens- Johnson syndrome); exfoliative erythroderma; mycosis fungoides. 3. Edematous States To induce diuresis or remission of proteinuria in nephrotic syndrome in adults with lupus erythematosus and in adults and pediatric populations, with idiopathic nephrotic syndrome, without uremia. 4. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; hypercalcemia associated with cancer; nonsuppurative thyroiditis. 5. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: ulcerative colitis; regional enteritis. 6. Hematologic Disorders Idiopathic thrombocytopenic purpura in adults; selected cases of secondary thrombocytopenia; acquired (autoimmune) hemolytic anemia; pure red cell aplasia; Diamond-Blackfan anemia. 7. Neoplastic Diseases For the treatment of acute leukemia and aggressive lymphomas in adults and children. 8. Nervous System Acute exacerbations of multiple sclerosis. 9. Ophthalmic Diseases Uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids; temporal arteritis; sympathetic ophthalmia. 10. Respiratory Diseases Symptomatic sarcoidosis; idiopathic eosinophilic pneumonias; fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy; asthma (as distinct from allergic asthma listed above under “Allergic States”), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, acute exacerbations of chronic obstructive pulmonary disease (COPD), and Pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV (+) individual who is also under treatment with appropriate anti-PCP antibiotics. Studies support the efficacy of systemic corticosteroids for the treatment of these conditions: allergic This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 4 bronchopulmonary aspergillosis, idiopathic bronchiolitis obliterans with organizing pneumonia. 11. Rheumatic Disorders As adjunctive therapy for short term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy); ankylosing spondylitis; acute and subacute bursitis; acute nonspecific tenosynovitis; acute gouty arthritis; epicondylitis. For the treatment of systemic lupus erythematosus, dermatomyositis (polymyositis), polymyalgia rheumatica, Sjogren’s syndrome, relapsing polychondritis, and certain cases of vasculitis. 12. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block, tuberculosis with enlarged mediastinal lymph nodes causing respiratory difficulty, and tuberculosis with pleural or pericardial effusion (appropriate antituberculous chemotherapy must be used concurrently when treating any tuberculosis complications); Trichinosis with neurologic or myocardial involvement; acute or chronic solid organ rejection (with or without other agents). CONTRAINDICATIONS: Systemic fungal infections. Hypersensitivity to the drug or any of its components. WARNINGS: General: In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated. Cardio-renal: Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Endocrine: Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Infections (General): Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 5 including viral, bacterial, fungal, protozoan or helminthic infection, in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect humoral or cellular immunity, or neutrophil function. These infections may be mild to severe, and, with increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of infection after it has already started. Infections (Viral): Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents should be considered. Ophthalmic: Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. Special Pathogens: Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Candida, Mycobacterium, Ameba, Toxoplasma, Pneumocystis, Cryptococus, Nocardia, etc. Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. Tuberculosis: The use of prednisolone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 6 If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy these patients should receive chemoprophylaxis. Vaccination: Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered, however, the response to such vaccines can not be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. PRECAUTIONS: General: The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with hypertension, congestive heart failure, or renal insufficiency. Endocrine: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Gastrointestinal: Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 7 lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy. Neuro-psychiatric: Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients: Patients should be warned not to discontinue the use of prednisolone sodium phosphate, USP, oral solution abruptly or without medical supervision, to advise any medical attendants that they are taking it, and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions: Drugs such as barbiturates, phenytoin, ephedrine, and rifampin, which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of prednisolone and require that the dosage of prednisolone sodium phosphate, USP, oral solution be increased. Increased activity of both cyclosporin and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Estrogens may decrease the hepatic metabolism of certain corticosteroids thereby increasing their effect. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 8 Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects. Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Concomitant use of aspirin (or other non-steroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., diuretics, amphotericin-B), patients should be observed closely for development of hypokalemia. Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Due to inhibition of antibody response, patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. If possible, routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued. Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Corticosteroids may suppress reactions to skin tests. Pregnancy: Teratogenic Effects: Pregnancy Category C. Prednisolone has been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which prednisolone has been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well controlled studies in pregnant women. Prednisolone sodium phosphate, USP, oral solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when prednisolone sodium phosphate, USP, oral solution is administered to a nursing woman. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 9 Pediatric Use: The efficacy and safety of prednisolone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisolone in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose. Geriatric Use: Clinical studies of prednisolone sodium phosphate, USP, oral solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with prednisolone sodium phosphate has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and appear to be dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e., ≤5 mg/day). Prednisolone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involutional osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisolone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Co-administration of bisphosphonates has been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment of corticosteroid-induced osteoporosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 10 It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. However, it is not clear whether dosing reductions would be necessary in elderly patients, since these pharmacokinetic alterations may be offset by age- related differences in responsiveness of target organs and/or less pronounced suppression of adrenal release of cortisol. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS: (listed alphabetically under each subsection): Cardiovascular: Hypertrophic cardiomyopathy in premature infants. Dermatologic: Facial erythema; increased sweating; impaired wound healing; may suppress reactions to skin tests; petechiae and ecchymoses; thin fragile skin; urticaria; edema. Endocrine: Decreased carbohydrate tolerance; development of cushingoid state; hirsutism; increased requirements for insulin or oral hypoglycemic agents in diabetic patients; manifestations of latent diabetes mellitus; menstrual irregularities; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; suppression of growth in children. Fluid and Electrolyte Disturbances: Congestive heart failure in susceptible patients; fluid retention; hypertension; hypokalemic alkalosis; potassium loss; sodium retention. Gastrointestinal: Abdominal distention; elevation in serum liver enzyme levels (usually reversible upon discontinuation); pancreatitis; peptic ulcer with possible perforation and hemorrhage; ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads; loss of muscle mass; muscle weakness; osteoporosis; pathologic fracture of long bones; steroid myopathy; tendon rupture; vertebral compression fractures. Neurological: Convulsions; headache; increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment; psychic disorders; vertigo. Ophthalmic: Exophthalmos; glaucoma; increased intraocular pressure; posterior subcapsular cataracts. Other: Increased appetite; malaise; nausea; weight gain. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 11 OVERDOSAGE: The effects of accidental ingestion of large quantities of prednisolone over a very short period of time have not been reported, but prolonged use of the drug can produce mental symptoms, moon face, abnormal fat deposits, fluid retention, excessive appetite, weight gain, hypertrichosis, acne, striae, ecchymosis, increased sweating, pigmentation, dry scaly skin, thinning scalp hair, increased blood pressure, tachycardia, thrombophlebitis, decreased resistance to infection, negative nitrogen balance with delayed bone and wound healing, headache, weakness, menstrual disorders, accentuated menopausal symptoms, neuropathy, fractures, osteoporosis, peptic ulcer, decreased glucose tolerance, hypokalemia, and adrenal insufficiency. Hepatomegaly and abdominal distention have been observed in children. Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy the dosage of prednisolone may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION: The initial dosage of prednisolone sodium phosphate, USP, oral solution may vary from 5 mL to 60 mL (5 to 60 mg prednisolone base) per day depending on the specific disease entity being treated. In situations of less severity, lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time, there is a lack of satisfactory clinical response, prednisolone sodium phosphate, USP, oral solution should be discontinued and the patient placed on other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of prednisolone sodium phosphate, USP, oral solution for a period of time consistent with the patient’s condition. If after long term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. In the treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day or 4 to 8 mg dexamethasone every other day for one month have been shown to be effective. In pediatric patients, the initial dose of prednisolone sodium phosphate, USP, oral solution may vary depending on the specific disease entity being treated. The range of initial doses is 0.14 to 2 mg/kg/day in three or four divided doses (4 to 60 mg/m2bsa/day). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 12 The standard regimen used to treat nephrotic syndrome in pediatric patients is 60 mg/m2/day given in three divided doses for 4 weeks, followed by 4 weeks of single dose alternate-day therapy at 40 mg/m2/day. The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic prednisone, prednisolone or methylprednisolone in children whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1-2 mg/kg/day in single or divided doses. It is further recommended that short course, or “burst” therapy, be continued until a child achieves a peak expiratory flow rate of 80% of his or her personal best or symptoms resolve. This usually requires 3 to 10 days of treatment, although it can take longer. There is no evidence that tapering the dose after improvement will prevent a relapse. For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids: Cortisone, 25 Triamcinolone, 4 Hydrocortisone, 20 Paramethasone, 2 Prednisolone, 5 Betamethasone, 0.75 Prednisone, 5 Dexamethasone, 0.75 Methylprednisolone, 4 These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered. HOW SUPPLIED: Prednisolone sodium phosphate, USP, oral solution is a colorless to light straw colored solution containing 6.7 mg prednisolone sodium phosphate (5 mg prednisolone base) per 5 mL (teaspoonful). NDC 65580-251-01 120 mL bottle Store at 4°-25°C (39°-77°F). May be refrigerated. Keep tightly closed and out of the reach of children. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-157/S-018 Page 13 Manufactured by: Celltech Manufacturing, Inc. Rochester, NY 14623 USA, for: Rochester, NY 14623 USA © 2004, Celltech Manufacturing, Inc. R539A Rev. 5/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.467626	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19157s018lbl.pdf', 'application_number': 19157, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,441	1 CALAN® SR (verapamil hydrochloride) Sustained-Release Oral Caplets DESCRIPTION CALAN SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist). CALAN SR is available for oral administration as light green, capsule-shaped, scored, film-coated tablets (caplets) containing 240 mg of verapamil hydrochloride; as light pink, oval, scored, film-coated tablets (caplets) containing 180 mg of verapamil hydrochloride; and as light violet, oval, film-coated tablets (caplets) containing 120 mg of verapamil hydrochloride. The caplets are designed for sustained release of the drug in the gastrointestinal tract; sustained-release characteristics are not altered when the caplet is divided in half. The structural formula of verapamil HCl is: Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil HCl is not chemically related to other cardioactive drugs. Inactive ingredients include alginate, carnauba wax, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, titanium dioxide, and coloring agents: 240 mg—D&C Yellow No. 10 Lake and FD&C Blue No. 2 Lake; 120 and 180 mg—iron oxide. CLINICAL PHARMACOLOGY CALAN (verapamil HCl) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Mechanism of action Essential hypertension: Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise, CALAN does not alter systolic cardiac function in patients with normal ventricular function. CALAN does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of CALAN. Other pharmacologic actions of CALAN include the following: CALAN dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine- induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of CALAN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate–pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. CALAN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, CALAN prolongs the effective refractory period within the AV node and slows AV conduction in a rate- related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, CALAN may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS). CALAN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. CALAN may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS). CALAN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 Pharmacokinetics and metabolism: With the immediate-release formulation, more than 90% of the orally administered dose of CALAN is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil HCl every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL, with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma level does exist. In early dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single-dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In multiple-dose studies under fasting conditions, the bioavailability, measured by AUC, of CALAN SR was similar to CALAN (immediate release); rates of absorption were of course different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg CALAN SR with food produced peak plasma verapamil concentrations of 79 ng/mL; time to peak plasma verapamil concentration of 7.71 hours; and AUC (0–24 hr) of 841 ng·hr/mL. When CALAN SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time to peak plasma verapamil concentration was 5.21 hours; and AUC (0–24 hr) was 1,478 ng·hr/mL. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak-to-trough ratio. Good correlation of dose and response is not available, but controlled studies of CALAN SR have shown effectiveness of doses similar to the effective doses of CALAN (immediate release). In healthy men, orally administered CALAN undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate-release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg·hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg·hr/dL). Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values (see PRECAUTIONS, Drug interactions). Hemodynamics and myocardial metabolism: CALAN reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with CALAN. In most patients, including those with organic cardiac disease, the negative inotropic action of CALAN is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (eg, pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS, Drug interactions). Pulmonary function: CALAN does not induce bronchoconstriction and, hence, does not impair ventilatory function. INDICATIONS AND USAGE CALAN SR is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. CONTRAINDICATIONS Verapamil HCl caplets are contraindicated in: 1. Severe left ventricular dysfunction (see WARNINGS) 2. Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) 5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS) 6. Patients with known hypersensitivity to verapamil hydrochloride WARNINGS Heart failure: Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta- adrenergic blocker (see PRECAUTIONS, Drug interactions). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. (Note interactions with digoxin under PRECAUTIONS) Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension. Elevated liver enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC- cardioversion. Cardioversion has been used safely and effectively after oral CALAN. Atrioventricular block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first- degree block or progressive development to second- or third-degree AV block, requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy, depending upon the clinical situation. Patients with hypertrophic cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS, Drug interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued. PRECAUTIONS General Use in patients with impaired hepatic function: Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out. Use in patients with attenuated (decreased) neuromuscular transmission: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission. Use in patients with impaired renal function: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE). Drug interactions HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. Beta-blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of CALAN use, the patient should be reassessed to avoid under-digitalization. Antihypertensive agents: Verapamil administered concomitantly with oral antihypertensive agents (eg, vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. Antiarrhythmic agents: Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 The electrophysiologic effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. Other agents: Alcohol: Verapamil has been found to inhibit ethanol elimination significantly, resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol (see CLINICAL PHARMACOLOGY, Pharmacokinetics and metabolism). Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully. Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin. Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline. Inhalation anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular blocking agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class. Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. Carcinogenesis, mutagenesis, impairment of fertility: An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor and delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing mothers: Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric use: Safety and efficacy of CALAN SR in pediatric patients below the age of 18 years have not been established. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Animal pharmacology and/or animal toxicology: In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater, and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not in the rat. Development of cataracts due to verapamil has not been reported in man. ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients: Constipation 7.3% Dyspnea 1.4% Dizziness 3.3% Bradycardia Nausea 2.7% (HR <50/min) 1.4% Hypotension 2.5% AV block Headache 2.2% (total 1°, 2°, 3°) 1.2% Edema 1.9% (2° and 3°) 0.8% CHF, Pulmonary …edema 1.8% Rash Flushing 1.2% 0.6% Fatigue 1.7% Elevated liver enzymes (see WARNINGS) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive system: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and lymphatic: ecchymosis or bruising. Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence. Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special senses: blurred vision, tinnitus. Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence. Treatment of acute cardiovascular adverse reactions: The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; eg, intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobutamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. OVERDOSAGE Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (eg, junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (eg, metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially CALAN SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time. In overdose, caplets of CALAN SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 g/hr for more than 24 hr) of calcium chloride. Verapamil cannot be Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. DOSAGE AND ADMINISTRATION Essential hypertension: The dose of CALAN SR should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCl, CALAN SR, given in the morning. Lower initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (eg, the elderly or small people). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of CALAN SR are evident within the first week of therapy. If adequate response is not obtained with 180 mg of CALAN SR, the dose may be titrated upward in the following manner: a) 240 mg each morning, b) 180 mg each morning plus 180 mg each evening; or 240 mg each morning plus 120 mg each evening, c) 240 mg every 12 hours. When switching from immediate-release CALAN to CALAN SR, the total daily dose in milligrams may remain the same. HOW SUPPLIED CALAN SR 120 mg caplets are light violet, oval, film coated, with CALAN debossed on one side and SR 120 on the other, supplied as: NDC Number Size 0025-1901-31 bottle of 100 CALAN SR 180 mg caplets are light pink, oval, scored, film coated, with CALAN debossed on one side and SR 180 on the other, supplied as: NDC Number Size 0025-1911-31 bottle of 100 CALAN SR 240 mg caplets are light green, capsule shaped, scored, film coated, with CALAN debossed on one side and SR 240 on the other, supplied as: NDC Number Size 0025-1891-31 bottle of 100 0025-1891-51 bottle of 500 Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 14 Store at 59° to 77°F (15° to 25°C) and protect from light and moisture. Dispense in tight, light-resistant containers. Manufactured for: G.D. Searle LLC Division of Pfizer, Inc NY, NY 10017 by: (120 mg and 180 mg caplets) Abbott Laboratories North Chicago, IL 60064 Pfizer, Inc Caguas, PR 00725 (240 mg caplets) Abbott GmbH & Co. KG Ludwigshafen, Germany LAB-0268-6.1 Revised October 2013 Reference ID: 3396627 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.596212	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019152s038lbl.pdf', 'application_number': 19152, 'submission_type': 'SUPPL ', 'submission_number': 38}
11,449	Voltaren® (diclofenac sodium enteric-coated tablets) Tablets of 25 mg, 50 mg, and 75 mg Rx only Prescribing Information DESCRIPTION Voltaren® (diclofenac sodium enteric-coated tablets) is a benzene- acetic acid derivative. Voltaren is available as delayed-release (enteric- coated) tablets of 25 mg (yellow), 50 mg (light brown), and 75 mg (light pink) for oral administration. The chemical name is 2-[(2,6- dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molec- ular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula The inactive ingredients in Voltaren include: hydroxypropyl methylcel- lulose, iron oxide, lactose, magnesium stearate, methacrylic acid copoly- mer, microcrystalline cellulose, polyethylene glycol, povidone, propylene glycol, sodium hydroxide, sodium starch glycolate, talc, titanium dioxide, D&C Yellow No. 10 Aluminum Lake (25-mg tablet only), FD&C Blue No. 1 Aluminum Lake (50-mg tablet only). CLINICAL PHARMACOLOGY Pharmacodynamics Voltaren® (diclofenac sodium enteric-coated tablets) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, anal- gesic, and antipyretic activities in animal models. The mechanism of action of Voltaren, like that of other NSAIDs, is not completely under- stood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%. Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20-48 yrs.) Coefficient of Mean Variation (%) Absolute 55 40 Bioavailability (%) [N = 7] Tmax (hr) 2.3 69 [N = 56] Oral Clearance 582 23 (CL/F; mL/min) [N = 56] Renal Clearance <1 — (% unchanged drug in urine) [N = 7] Apparent Volume of 1.4 58 Distribution (V/F; L/kg) [N = 56] Terminal Half-life (hr) 2.3 48 [N = 56] Distribution The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac is more than 99% bound to human serum proteins, prima- rily to albumin. Serum protein binding is constant over the concentration range (0.15-105 mg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. However, diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion. One diclofenac metabolite 4'-hydroxy- diclofenac has very weak pharmacologic activity. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Special Populations Pediatric: The pharmacokinetics of Voltaren has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Voltaren elimination, so patients with hepatic disease may require reduced doses of Voltaren compared to patients with normal hepatic function. Renal Insufficiency: Diclofenac pharmacokinetics has been investi- gated in subjects with renal insufficiency. No differences in the pharma- cokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60- 90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimi- nation rate were comparable to those in healthy subjects. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Voltaren® (diclofenac sodium enteric-coated tablets) and other treatment options before deciding to use Voltaren. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Voltaren is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For acute or long-term use in the relief of the signs and symptoms of ankylosing spondylitis CONTRAINDICATIONS Voltaren® (diclofenac sodium enteric-coated tablets) is contraindicated in patients with known hypersensitivity to diclofenac. Voltaren should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma). Voltaren is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardio- vascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin miti- gates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexist- ing hypertension, either of which may contribute to the increased inci- dence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Voltaren® (diclofenac sodium enteric-coated tablets), should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Voltaren should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including Voltaren, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perfo- ration of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or with- out warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID ther- apy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of ther- apy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagu- lants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinua- tion of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Caution should be used when initiating treatment with Voltaren in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Voltaren in patients with advanced renal disease. Therefore, treatment with Voltaren is not recommended in these patients with advanced renal disease. If Voltaren therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Voltaren. Voltaren should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma.) Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Voltaren, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Voltaren should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Voltaren® (diclofenac sodium enteric-coated tablets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerba- tion. Patients on prolonged corticosteroid therapy should have their ther- apy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Voltaren in reducing fever and inflam- mation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Voltaren. These laboratory abnor- malities may progress, may remain unchanged, or may be transient with continuing therapy. Based on this experience, in patients on chronic treatment with Voltaren, periodic monitoring of transaminases is recom- mended (see PRECAUTIONS, Laboratory Tests). Notable elevations of ALT or AST (approximately three or more times the upper limit of nor- mal) have been reported in approximately 2%-4% of patients, including marked elevations (eight or more times the upper limit of normal) in about 1% of patients in clinical trials with diclofenac. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal out- comes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Voltaren. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Voltaren should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Voltaren. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients Cl NH CH2COONa Cl ©Novartis T2006-07 Voltaren® (diclofenac sodium enteric-coated tablets) Voltaren® (diclofenac sodium enteric-coated tablets) Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardio- vascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.) • Voltaren® (diclofenac sodium enteric-coated tablets) is contraindi- cated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and per- foration of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda on long-term treatment with NSAIDs, including Voltaren, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Voltaren who may be adversely affected by alter- ations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti- inflammatory drugs has been reported in such aspirin-sensitive patients, Voltaren should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before ini- tiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dis- pensed. 1. Voltaren, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Voltaren, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspep- sia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. Voltaren, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reac- tion (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, Voltaren should be avoided because it will cause premature closure of the ductus arteriosus. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including Voltaren, the CBC and a chemistry profile (including transaminase lev- els) should be checked periodically. If clinical signs and symptoms con- sistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Voltaren should be discontinued. Drug Interactions Aspirin: When Voltaren is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Cyclosporine: Voltaren, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Voltaren may increase cyclosporine’s nephro- toxicity. Caution should be used when Voltaren is administered concomi- tantly with cyclosporine. ACE Inhibitors: Reports suggest that NSAIDs may diminish the anti- hypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide: Clinical studies, as well as post-marketing observations, have shown that Voltaren can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of seri- ous GI bleeding higher than users of either drug alone. Pregnancy Teratogenic Effects: Pregnancy Category C Reproductive studies conducted in rats and rabbits have not demon- strated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Voltaren on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS In patients taking Voltaren® (diclofenac sodium enteric-coated tablets), or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tin- nitus. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachy- cardia, syncope Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastri- tis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarc- tion, palpitations, vasculitis Digestive System: colitis, eructation, liver failure, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, ery- thema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care fol- lowing a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodial- ysis, or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Voltaren® (diclofenac sodium enteric-coated tablets) and other treatment options before deciding to use Voltaren. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Voltaren, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of osteoarthritis, the recommended dosage is 100-150 mg/day in divided doses (50 mg b.i.d. or t.i.d., or 75 mg b.i.d.). For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses (50 mg t.i.d. or q.i.d., or 75 mg b.i.d.). For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day, administered as 25 mg q.i.d., with an extra 25-mg dose at bedtime if necessary. Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated tablets); Voltaren®-XR (diclofenac sodium extended- release tablets); Cataflam® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same. HOW SUPPLIED Voltaren® (diclofenac sodium enteric-coated tablets) 25 mg – yellow, biconvex, triangular-shaped, enteric-coated tablets (imprinted VOLTAREN 25 on one side in black ink) Bottles of 100 . . . . . . . . . . . . . . . . . . . .NDC 0028-0258-01 50 mg – light brown, biconvex, triangular-shaped, enteric-coated tablets (imprinted VOLTAREN 50 on one side in black ink) Bottles of 100 . . . . . . . . . . . . . . . . . . . .NDC 0028-0262-01 75 mg – light pink, biconvex, triangular-shaped, enteric-coated tablets (imprinted VOLTAREN 75 on one side in black ink) Bottles of 100 . . . . . . . . . . . . . . . . . . . .NDC 0028-0264-01 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). T2006-07 REV: JANUARY 2006 Printed in U.S.A. 5000671 Manufactured by: Mova Pharmaceuticals Corporation Caguas, Puerto Rico 00726 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 Voltaren® (diclofenac sodium enteric-coated tablets) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time dur- ing treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” • drinking alcohol and “anticoagulants” • older age • longer use • having poor health • smoking NSAID medicines should only be used: • exactly as prescribed • for the shortest time needed • at the lowest dose possible for your treatment What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all of your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your health- care provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbiprofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 * Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC label warns that long term continuous use may increase the risk of heart attack or stroke. This Medication Guide has been approved by the U.S. Food and Drug Administration. Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • skin rash or blisters with fever • unusual weight gain • swelling of the arms and legs, hands and feet This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:16.982072	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019201s036lbl.pdf', 'application_number': 19201, 'submission_type': 'SUPPL ', 'submission_number': 36}
11,448	PROVOCHOLINECI brand of methacholine chloride POWDER FOR INHALATION NOT FOR INJECTION PROVOCHOLlNE'" (METHACHOLINE CHLORIDE POWDER FOR INHALATION) IS A BRONCHOCONSTRICTOR AGENT FOR DIAGNOSTIC PURPOSES ONLY AND SHOULD NOT BE USED AS A THERAPEUTIC AGENT. PROVOCHOLlNE'" INHALATION CHALLENGE SHOULD BE PERFORMED ONLY UNDER THE SUPERVISION OF APHYSICIANTRAINED INAND THOROUGHLY FAMILIAR WITH ALL ASPECTS OF THE TECHNIQUE OF METHACHOLINE CHALLENGE, ALL CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, AND THE MANAGEMENT OF RESPIRATORY DISTRESS. EMERGENCY EQUIPMENT AND MEDICATION SHOULD BE IMMEDIATELY AVAILABLE TO TREAT ACUTE RESPIRATORY DISTRESS. PROVOCHOLlNE'" SHOULD BE ADMINISTERED ONLY BY INHALATION. SEVERE BRONCHOCONSTRICTION AND REDUCTION IN RESPIRATORY FUNCTION CAN RESULT FROM THE ADMINISTRATION OF PROVOCHOLlNE"'. PATIENTS WITH SEVERE HYPERREACTIVITY OF THE AIRWAYS CAN EXPERIENCE BRONCHOCONSTRICTION AT A DOSAGE AS LOW AS 0.025 MG/ML (0.125 CUMULATIVE UNITS). IF SEVERE BRONCHOCONSTRICTION OCCURS, IT SHOULD BE REVERSED IMMEDIATELY BY THE ADMINISTRATION OF A RAPID ACTING INHALED BRONCHODILATOR AGENT (BETA AGONIST). BECAUSE OF THE POTENTIAL FOR SEVERE BRONCHOCONSTRICTION, PROVOCHOLlNE'" CHALLENGE SHOULD NOT BE PERFORMED IN ANY PATIENT WITH CLINICALLY APPARENT ASTHMA, WHEEZING, OR VERY LOW BASELINE PULMONARY FUNCTION TESTS (e.g., FEV1 LESS THAN 1 TO 1.5 LITER OR LESS THAN 70% OF THE PREDICTED VALUES). PLEASE CONSULT STANDARD NOMOGRAMS FOR PREDICTED VALUES.1 DESCRIPTION: Provocholine'" (methacholine chloride powder for inhalation) is a parasympathomimetic (c h 0 Ii n erg i c) bronchoconstrictor agent to be administered in solutiOn only, by inhalation, for diagnostic purposes. Each 20 mL vial contains 100 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). See DOSAGE AND ADMINISTRATION for dilution procedures, concentrations and schedule of administration. Chemically, methacholine chloride (the active ingredient) is 1-propanaminium, 2-(acetyloxy) N,N,N, - trimethyl,-chloride. It is a white to practically white deliquescent compound, soluble in water. Methacholine chloride has an empirical formula of CsH1sCIN02, a calculated molecular weight of 195.69, and the following structural formula: I CI- CHs L CHsCOOCHCH2N (CHs)s J CLINICAL PHARMACOLOGY: Methacholine chloride is the ß-methyl homolog of acetylcholine and differs from the latter primarily in its greater duration and selectivity of action. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Bronchoconstriction occurs when the vagus nerve is stimulated and acetylcholine is released from the nerve endings. Muscle constriction is essentially confined to the local site of release because acetylcholine is rapidly inactivated by acetylcholinesterase. Compared with acetylcholine, methacholine chloride is more slowly hydrolyzed by acetylcholinesterase and is almost totally resistant to inactivation by nonspecific cholinesterase or pseudocholinesterase. When a sodium chloride solution containing methacholine chloride is inhaled, subjects with asthma are markedly more sensitive to methacholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacologic basis for the Provocholine'" (methacholine chloride powder for inhalation) inhalation diagnostic challenge. However, it should be recognized that methacholine challenge may occasionally be positive after influenza, upper respiratory infections or immunizations, in very young or very old patients, or in patients with chronic lung disease (cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease). The challenge may also be positive in patients with allergic rhinitis without asthma, in smokers, in patients after exposure to air pollutants, or in patients who have had or wil in the future develop asthma. There are no metabolic and pharmacokinetic data available on methacholine chloride. INDICATIONS AND USAGE: Provocholine'" (methacholine chloride powder for inhalation) is indicated for the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. CONTRAINDICATIONS: Provocholine'" (methacholine chloride powder for inhalation) is contraindicated in patients with known hypersensitivity to this drug or to other parasympathomimetic agents. Repeated administration of Provocholine'" by inhalation other than on the day that a patient undergoes challenge with increasing doses is contraindicated. Inhalation challenge should not be performed in patients receiving any beta-adrenergic blocking agent because in such patients responses to methacholine chloride can be exaggerated or prolonged, and may not respond as readily to accepted modalities of treatment (see WARNINGS box). PRECAUTIONS: General: Administration of Provocholine'" (methacholine chloride powder for inhalation) to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should be undertaken only if the phYSician feels benefit to the individual outweighs the potential risks. Information for Patients: To assure the safe and effective use of Provocholine'" inhalation challenge, the following instructions and information should be given to patients: 1. Patients should be instructed regarding symptoms that may occur as a result of the test and how! such symptoms can be managed. ' 2. A female patient should inform her physician if she is pregnant, or the date of her last onset of menses, or the date and result of her last pregnancy test. (See PRECAUTIONS: Pregnancy.) Carcinogenesis, Mutagenesis, ImpairmentofFertility: There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertilty. Pregnancy: Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have not been conducted with methacholine chloride. It is not known whether methacholine chloride can cause fetal harm when administered to a pregnant patient or affect reproductive capacity. Methacholine chloride should be given to a pregnant woman only if clearly needed. IN FEMALES OF CHILDBEARING POTENTIAL, PROVOCHOLlNE'" INHALATION CHALLENGE SHOULD BE PERFORMED EITHER WITHIN TEN DAYS FOLLOWING THE ONSET OF MENSES OR WITHIN 2 WEEKS OF A NEGATIVE PREGNANCY TEST. Nursing Mothers: Provocholine'" inhalation challenge should not be administered to a nursing mother since it is not known whether methacholine chloride when inhaled is excreted in breast milk. Pediatric Use: The safety and efficacy of Provo choline'" inhalation challenge have not been established in children below the age of 5 years. ADVERSE REACTIONS: Adverse reactions associated with 153 inhaled methacholine chloride challenges include one occurrence each of headache, throat irritation, Iightheadedness and itching. Provocholine'" (methacholine chloride powder for inhalation) is to be administered only by inhalation. When administered orally or by injection, methacholine chloride is reported to be associated with nausea and vomiting, substernal pain or pressure, hypotension, fainting and transient complete heart block. (See OVERDOSAGE.) OVERDOSAGE: Provocholine'" (methacholine i chloride powder for inhalation) is to be administered only by inhalation. When administered orally or by injection, overdosage with methacholine chloride can result in a syncopal reaction, with cardiac arrest and loss of consciousness. Serious toxic reactions should be treated with 0.5 mg to 1 mg of atropine sulfate, administered 1M or IV. The acute (24 hour) oral LD50 of methacholine chloride and related compounds is 1100 mg/kg in the mouse and 750 mg/kg in the rat. Cynomolgus monkeys were exposed to a 2% (20 mg/mL) aerosol of methacholine chloride in acute (10 minute) and subchronic (7 day) inhalation toxicity studies. In the former study, animals exposed to the aerosol for up to 10 minutes demonstrated an increase in respiratory rate and decrease in tidal volume after 30 seconds. These changes peaked at 2 minutes and were followed by a rise in pulmonary resistance and a decrease in compliance. Pulmonary function returned to normal 20 to 25 minutes after exposure ended. In the 7 day study, monkeys were given daily inhalations equivalent to the maximum and roughly five times the maximum standard human dose. Although the typical pulmonary response/ recovery sequence was observed, distinct changes in airway resistance were noted at the end of the study. These changes were not rapidly reversed in the maximum equivalent standard dose group, which was observed for 9 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION: Before Provocholine'" (methacholine chloride powder for inhalation) inhalation challenge is begun, baseline pulmonary function tests must be performed. A subject to be challenged must have an FEV1 of at least 70% of the predicted value. The target level for a positive challenge is a 20% reduction in the FEV1 compared with the baseline value after inhalation of the control sodium chloride solution (Note: Use the same diluent that the Provocholine'" powder has been reconstituted with for the baseline spirometry). This target value should be calculated and recorded before Provocholine'" challenge is started. Dilutions: (Note: Do not inhale powder. Do not handle this material if you have asthma or hay fever.) All dilutions should be made with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) using sterile, empty USP Type I borosilcate glass vials. After adding the sodium chloride solution, §hake each vial to obtain a clear solution (Note: When preparing dilutions, use only the same kind of diluent to prepare all concentrations). DILUTION SEQUENCE-MULTIPLE PATIENT TESTING (2-5 PATIENTS) ¡REQUIRES 2 VIALS OF PROVOCHOLlNE"j Vials Concen trations Ai &A2 Add 4 mL of 0.9% sodium 25 chloride injection or 0.9% mg/mL sodium chloride injection containing 0.4% phenol (pH 7.0) to each of two 20 mL vials containing 100 mg of Provocholine'" (methacholine chloride powder for inhalation). These wil be designated vials A and A2. B Remove 3 mL from vial A, 10 transfer to another vial and mg/mL add 4.5 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). . U_ -This Is vial B. C Remove 1 mL from vial A2, 2.5 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial C. D Remove 1 mL from vial C, 0.25 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial D. E Remove 1 mL from vial D, 0.025 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial E. Vial E must be prepared on the day of challenge. DILUTION SEQUENCE SINGLE PATIENT TESTING Vials Concen trations A Add 4 mL of 0.9% sodium 25 chloride injection or 0.9% mg/mL sodium chloride injection containing 0.4% phenol (pH 7.0) to the 20 mL vial containing 100 mg of Provocholine"'(methacholine chloride powder for inhalation). This is vial A. B Remove 1 mL from vial A, 10 transfer to another vial and mg/mL add 1.5 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial B. C Remove 1 mL from vial A, 2.5 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial C. D Remove 1 mL from vial C, 0.25 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial D. E Remove 1 mL from vial D, 0.025 transfer to another vial and add mg/mL 9 mL of 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0). This is vial E. Vial E must be prepared on the day of the challenge. Dilutions A through D should be stored at 36° to 46°F (2° to 8°C) in a refrigerator and can be stored for not more than 2 weeks. (The unreconstituted powder should be stored at 59°F to 86°F (15° to 30°C)J. After this time, discard the vials and prepare new dilutions. Freezing does not affect the stabilty of dilutions A through D. Vial E must be prepared on the day of challenge. A sterile bacterial-retentive filter (porosity 0.22 ¡.m) should be used when transferring a solution from each vial (at least 2 mL) to a nebulizer. Procedure: A standardized procedure for inhalation has been developed. The challenge is performed by giving a subject ascending serial concentrations of Provocholine"'. At each concentration, five breaths are administered by a nebulizer that permits intermittent delivery time of 0.6 seconds by a breath-actuated timing device (dosimeter). At each of five inhalations of a serial concentration, the subject begins at functional residual capaCity (FRC) and slowly and completely inhales the dose delivered. Within 5 minutes, FEV1 values are determined. The procedure ends either when there is a 20% or greater reduction in the FEV1 compared with the baseline sodium chloride solution value (i.e., a positive response) or if 188.88 total cumulative units have been administered (see table below) and the FEV1 has been reduced by 14 % or less (i.e., a negative response). If there is a reduction of 15% to 19% in the FEV, compared with baseline, either the challenge may be repeated at that concentration or a higher concentration may be given as long as the dosage administered does not result in total cumulative units exceeding 188.88. The following is a suggested schedule for the administration of Provocholine'" (methacholine chloride powder for inhalation) challenge. Cumulative units are calculated by multiplying the number of breaths by the concentration administered. Total cumulative units is the sum of cumulative units for each concentration administered. Cumulative Total Serial Number of Units per Cumulative Concentration Breaths Concentration Units 0.025 mg/mL 5 0.125 0.125 0.25 mg/mL 5 1.25 1.375 2.5 mg/mL 5 12.5 13.88 10.0 mg/mL 5 50.0 63.88 25.0 mg/mL 5 125. 188.88 An inhaled beta-agonist may be administered after Provocholine'" challenge to expedite the return of the FEV1 to baseline and to relieve the discomfort of the subject. Most patients revert to normal pulmonary function within 5 minutes following bronchodilators or within 30 to 45 minutes without any bronchodilator. HOW SUPPLIED: 20 mL amber vials containing 100 mg of methacholine chloride powder which is to be reconstituted with 0.9% sodium chloride injection or 0.9% sodium chloride injection containing 0.4% phenol (pH 7.0) - boxes of 12 (NDC 64281-100-12) or boxes of 6 (NDC 64281-00-06). Store the powder at 59° to 86°F (15° to 30°C). Refrigerate the reconstituted solutions (dilutions A-D) at 36° to 46°F (2° to 8°C) for not more than 2 weeks. Dilution E must be prepared on the day of the challenge. REFERENCE: 1. Morris JF, Koski WA, Johnson LC. Spirometric standards for healthy non-smoking adults. Am Rev Resp Dis. Jan 1971; 103: 57-67. fQethapharm Methapharm Inc. 81 Sinclair Boulevard Brantford, Ontario, Canada N3S 7X6 Toll Free: 800.287.7686 Tel: 519.751.3602 Fax: 519.751.9149 Email: sales~methapharm.com Web: www.methapharm.com January 2008 - PP/R-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:17.009895	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019193s013lbl.pdf', 'application_number': 19193, 'submission_type': 'SUPPL ', 'submission_number': 13}
11,447	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:17.111852	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/019190s036lbl.pdf', 'application_number': 19190, 'submission_type': 'SUPPL ', 'submission_number': 36}
11,450	company logo Voltaren® (diclofenac sodium enteric-coated tablets) Tablets of 75 mg Rx only Prescribing Information CARDIOVASCULAR RISK • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.) • Voltaren® (diclofenac sodium enteric-coated tablets) is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). GASTROINTESTINAL RISK • NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.) DESCRIPTION Voltaren® (diclofenac sodium enteric-coated tablets) is a benzene-acetic acid derivative. Voltaren is available as delayed-release (enteric-coated) tablets of 75 mg (light pink) for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula The inactive ingredients in Voltaren include: hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, povidone, propylene glycol, sodium hydroxide, sodium starch glycolate, talc, titanium dioxide. CLINICAL PHARMACOLOGY Pharmacodynamics Voltaren® (diclofenac sodium enteric-coated tablets) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Voltaren, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%. Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20-48 yrs.) Coefficient of Mean Mean Variation (%) Absolute 55 40 Bioavailability (%) [N = 7] Tmax (hr) 2.3 69 [N = 56] Oral Clearance (CL/F; mL/min) [N = 56] Renal Clearance (% unchanged drug in urine) [N = 7] Apparent Volume of 582 <1 1.4 23 — 58 Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Distribution (V/F; L/kg) [N = 56] Terminal Half-life (hr) 2.3 48 [N = 56] Distribution The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 μg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Metabolism Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3' hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy- diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours Drug Interactions When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS, Drug Interactions). Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Special Populations Pediatric: The pharmacokinetics of Voltaren has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Voltaren elimination, so patients with hepatic disease may require reduced doses of Voltaren compared to patients with normal hepatic function. Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Voltaren® (diclofenac sodium enteric-coated tablets) and other treatment options before deciding to use Voltaren. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Voltaren is indicated: • For relief of the signs and symptoms of osteoarthritis • For relief of the signs and symptoms of rheumatoid arthritis • For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis CONTRAINDICATIONS Voltaren® (diclofenac sodium enteric-coated tablets) is contraindicated in patients with known hypersensitivity to diclofenac. Voltaren should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic Reactions, and PRECAUTIONS, Preexisting Asthma). Voltaren is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, GI Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Voltaren® (diclofenac sodium enteric-coated tablets), should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Voltaren should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including Voltaren, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Caution should be used when initiating treatment with Voltaren in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Voltaren in patients with advanced renal disease. Therefore, treatment with Voltaren is not recommended in these patients with advanced renal disease. If Voltaren therapy must be initiated, close monitoring of the patient's renal function is advisable. Hepatic Effects Elevations of one or more liver tests may occur during therapy with Voltaren. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Voltaren should be discontinued immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with Voltaren, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Voltaren with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin triad and in patients without known sensitivity to NSAIDs or known prior exposure to Voltaren. Voltaren should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma.) Anaphylaxis-type reactions have been reported with NSAID products, including with diclofenac products, such as Voltaren. Emergency help should be sought in cases where an anaphylactic reaction occurs. Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin Reactions NSAIDs, including Voltaren, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Voltaren should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Voltaren® (diclofenac sodium enteric-coated tablets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Voltaren in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Voltaren. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Voltaren, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Voltaren who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Voltaren should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Voltaren, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Voltaren, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. Voltaren, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy (see WARNINGS, Hepatic Effects). 6. Patients should be informed of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactic Reactions). 7. In late pregnancy, as with other NSAIDs, Voltaren should be avoided because it will cause premature closure of the ductus arteriosus. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long- term treatment with NSAIDs, including Voltaren, the CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Voltaren should be discontinued. Drug Interactions Aspirin: When Voltaren is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Cyclosporine: Voltaren, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Voltaren may increase cyclosporine’s nephrotoxicity. Caution should be used when Voltaren is administered concomitantly with cyclosporine. ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide: Clinical studies, as well as postmarketing observations, have shown that Voltaren can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. CYP2C9 Inhibitors or Inducers: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers; a dosage adjustment may be warranted (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions). Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Teratogenic Effects: Pregnancy Category C Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nonteratogenic Effects: Because of the known effects of nonsteroidal anti inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Voltaren on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS In patients taking Voltaren® (diclofenac sodium enteric-coated tablets), or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses: blurred vision Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis. Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Voltaren® (diclofenac sodium enteric-coated tablets) and other treatment options before deciding to use Voltaren. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Voltaren, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of osteoarthritis, the recommended dosage is 100-150 mg/day in divided doses (50 mg b.i.d. or t.i.d., or 75 mg b.i.d.). For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses (50 mg t.i.d. or q.i.d., or 75 mg b.i.d.). For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day, administered as 25 mg q.i.d., with an extra 25-mg dose at bedtime if necessary. Different formulations of diclofenac [Voltaren® (diclofenac sodium enteric-coated tablets); Voltaren®-XR (diclofenac sodium extended-release tablets); Cataflam® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same. HOW SUPPLIED Voltaren® (diclofenac sodium enteric-coated tablets) 75 mg - light pink, biconvex, triangular-shaped, enteric-coated tablets (imprinted VOLTAREN 75 on one side in black ink) Bottles of 100.............................................................................................. NDC 0028-0264-01 Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE FOR NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called "corticosteroids" and "anticoagulants" • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: Other side effects include: • heart attack • stomach pain Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pains • flu-like symptoms • vomit blood Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbirofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 * Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Novartis. This Medication Guide has been approved by the U.S. Food and Drug Administration. REV: February 2011 T2009-34/T2009-35 company logo Manufactured by: Mova Pharmaceuticals Corporation Caguas, Puerto Rico 00726 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 © Novartis Reference ID: 2909327 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:17.116394	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019201s039s040lbl.pdf', 'application_number': 19201, 'submission_type': 'SUPPL ', 'submission_number': 39}
11,453	NDA 19-216/SCP-021 NDA 19-216/SLR-022 Page 3 FML FORTE® (fluorometholone ophthalmic suspension, USP) 0.25% sterile DESCRIPTION FML FORTE® sterile ophthalmic suspension is a topical anti-inflammatory product for ophthalmic use. Chemical Name: Fluorometholone: 9-Fluoro-11ß, 17-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione. Structural Formula: HO O CH3 CH3 CH3 H H H CH3 OH CO H F fluorometholone Contains: Active: fluorometholone 0.25%. Preservative: benzalkonium chloride 0.005%. Inactives: edetate disodium; polysorbate 80; polyvinyl alcohol 1.4%; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH. FML Forte® suspension is formulated with a pH from 6.2 to 7.5. CLINICAL PHARMACOLOGY Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-216/SCP-021 NDA 19-216/SLR-022 Page 4 Corticosteroids are capable of producing a rise in intraocular pressure. In clinical studies of documented steroid-responders, fluorometholone demonstrated a significantly longer average time to produce a rise in intraocular pressure than dexamethasone phosphate; however, in a small percentage of individuals a significant rise in intraocular pressure occurred within one week. The ultimate magnitude of the rise was equivalent for both drugs. INDICATIONS AND USAGE FML FORTE® suspension is indicated for the treatment of corticosteroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe. CONTRAINDICATIONS FML FORTE® suspension is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. FML FORTE® suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. WARNINGS Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication. If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended. PRECAUTIONS This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-216/SCP-021 NDA 19-216/SLR-022 Page 5 General: The initial prescription and renewal of the medication order beyond 20 milliliters of FML FORTE® suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated. As fungal infections of the cornea are particularly prone to develop coincidentally with long- term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, intraocular pressure should be monitored (see WARNINGS). Information for Patients: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children. Carcinogenesis, mutagenesis, impairment of fertility: No studies have been conducted in animals or in humans to evaluate the possibility of these effects with fluorometholone. Pregnancy: Teratogenic effects. Pregnancy Category C: Fluorometholone has been shown to be embryocidal and teratogenic in rabbits when administered in low multiples of the human ocular dose. Fluorometholone was applied ocularly to rabbits daily on days 6-18 of gestation, and dose-related fetal loss and fetal abnormalities including cleft palate, deformed rib cage, anomalous limbs and neural abnormalities such as encephalocele, craniorachischisis, and spina bifida were observed. There are no adequate and well-controlled studies of fluorometholone in pregnant women, and it is not known whether fluorometholone can cause fetal harm when administered to a pregnant woman. Fluorometholone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from fluorometholone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-216/SCP-021 NDA 19-216/SLR-022 Page 6 Pediatric Use: Safety and effectiveness in infants below the age of two years have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing. Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used. (see WARNINGS). Other adverse events reported with the use of FML FORTE® include transient burning and stinging upon instillation, ocular irritation, taste perversion and visual disturbance (blurry vision). DOSAGE AND ADMINISTRATION Instill one drop into the conjunctival sac two to four times daily. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days, the patient should be re-evaluated (see PRECAUTIONS). The dosing of FML FORTE® suspension may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of applications. HOW SUPPLIED FML FORTE® (fluorometholone ophthalmic suspension, USP) 0.25% is supplied sterile in opaque white LDPE plastic bottles with droppers with white high impact polystyrene (HIPS) caps as follows: 10 mL in 15 mL bottle - NDC 11980-228-10 5 mL in 10 mL bottle - NDC 11980-228-05 15 mL in 15 mL bottle - NDC 11980-228-15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-216/SCP-021 NDA 19-216/SLR-022 Page 7 Note: Store at or below 25˚C (77˚F); protect from freezing. Shake well before using. Rx Only Revised June 2004 © 2001Allergan, Inc. Irvine, CA 92612, U.S.A. 6951X ® Marks owned by Allergan, Inc. 71744US10P This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Linda Ng 1/10/2006 01:12:56 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:17.539214	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019216s021s022lbl.pdf', 'application_number': 19216, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,451	---------- THEOPHYLLINE 800 MG IN 5% DEXTROSE INJECTION, USP - theophylline injection, solution THEOPHYLLINE 400 MG IN 5% DEXTROSE INJECTION, USP - theophylline injection, solution THEOPHYLLINE 200 MG IN 5% DEXTROSE INJECTION, USP - theophylline injection, solution Hospira, Inc. THEOPHYLLINE 200, 400 AND 800 mg in 5% Dextrose Injection, USP Flexible Plastic Container Rx only DESCRIPTION Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula: Chemical Structure The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17. Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose sugar freely soluble in water. It has the following structural formula: Chemical Structure The molecular weight is 198.17. Water for Injection, USP is chemically designated H2O. Theophylline 200, 400 and 800 mg in 5% Dextrose Injection, USP are sterile, nonpyrogenic solutions of theophylline, anhydrous and dextrose in water for injection. See Table in HOW SUPPLIED for summary of contents and characteristics of these solutions. The solutions contain no bacteriostatic, antimicrobial agent or added buffer and are intended only for use as a single-dose administration. When smaller doses are required, the unused portion should be discarded. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain of its chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. CLINICAL PHARMACOLOGY Mechanism of Action: page 1 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV), while nonbronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. Serum Concentration-Effect Relationship: Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control and pulmonary function has been found in most studies to require serum theophylline concentrations >10 mcg/ mL. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining the average serum theophylline concentration between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events. Pharmacokinetics: Overview The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients receiving intravenous theophylline (e.g., at 24-hr. intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS,Effects on Laboratory Tests). Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.¶ Population characteristics Total body clearance* mean (range)†† (mL/kg/min) Half-life mean (range)†† (hr) Age Premature neonates postnatal age 3-15 days postnatal age 25-57 days 0.29 (0.09-0.49) 0.64 (0.04-1.2) 30 (17-43) 20 (9.4-30.6) Term infants postnatal age 1-2 days postnatal age 3-30 weeks NR† NR† 25.7 (25-26.5) 11 (6-29) Pediatric patients 1-4 years 4-12 years 13-15 years 16-17 years 1.7 (0.5-2.9) 1.6 (0.8-2.4) 0.9 (0.48-1.3) 1.4 (0.2-2.6) 3.4 (1.2-5.6) NR† NR† Adults (16-60 years) otherwise healthy nonsmoking asthmatics 0.65 (0.27-1.03) 8.7 (6.1-12.8) Elderly (>60 years) nonsmokers with normal cardiac, liver, and renal function 0.41 (0.21-0.61) 9.8 (1.6-18) page 2 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Concurrent illness or altered physiological state Acute pulmonary edema 0.33 (0.07-2.45) 19 (3.1-8.2) COPD- >60 years, stable nonsmoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6) COPD with cor pulmonale 0.48 (0.08-0.88) NR† Cystic fibrosis (14-28 years) 1.25 (0.31-2.2) 6.0 (1.8-10.2) Fever associated with acute viral respiratory illness (pediatric patients 9-15 years) NR† 7.0 (1.0-13) Liver disease- cirrhosis acute hepatitis cholestasis 0.31 (0.1-0.7) 0.35 (0.25-0.45) 0.65 (0.25-1.45) 32 (10-56) 19.2 (16.6-21.8) 14.4 (5.7-31.8) Pregnancy- 1st trimester 2nd trimester 3rd trimester NR† NR† NR† 8.5 (3.1-13.9) 8.8 (3.8-13.8) 13.0 (8.4-17.6) Sepsis with multi-organ failure 0.47 (0.19-1.9) 18.8 (6.3-24.1) Thyroid disease- hypothyroid hyperthyroid 0.38 (0.13-0.57) 0.8 (0.68-0.97) 11.6 (8.2-25) 4.5 (3.7-5.6) ¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. * Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations < 20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. †† Reported range or estimated range (mean ±2 SD) where actual range not reported. † NR = not reported or not reported in a comparable format. ** Median Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline. Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding may have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic page 3 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL. Metabolism In adults and pediatric patients beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3 dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, nonlinearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this nonlinearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes. Excretion In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and pediatric patients >3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (see WARNINGS). Serum Concentrations at Steady State In a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. In nonsmoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average pediatric patient (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/kg/hr. (See DOSAGE AND ADMINISTRATION.) Special Populations (See Table I for mean clearance and half-life values) Geriatrics The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs.) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS). Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION). Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy. Race Pharmacokinetic differences in theophylline clearance due to race have not been studied. Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end- stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose page 4 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS). Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS). Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS). Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to nonsmoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance. Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS). Miscellaneous Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis. CLINICAL STUDIES: Inhaled beta-2 selective agonists and systemically administered corticosteroids are the treatments of first choice for management of acute exacerbations of asthma. The results of controlled clinical trials on the efficacy of adding intravenous theophylline to inhaled beta-2 selective agonists and systemically administered corticosteroids in the management of acute exacerbations of asthma have been conflicting. Most studies in patients treated for acute asthma exacerbations in an emergency department have shown that addition of intravenous theophylline does not produce greater bronchodilation and increases the risk of adverse effects. In contrast, other studies have shown that addition of intravenous theophylline is beneficial in the treatment of acute asthma exacerbations in patients requiring hospitalization, particularly in patients who are not responding adequately to inhaled beta-2 selective agonists. In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements. INDICATIONS AND USAGE Intravenous theophylline is indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis. CONTRAINDICATIONS Theophylline is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product. WARNINGS Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. If the infusion rate is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age page 5 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Neonates (term and premature) Pediatric patients <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor pulmonale Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants < 3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin)(see PRECAUTIONS, Drug Interactions, Table II). When Signs or Symptoms of Theophylline Toxicity Are Present: Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately. Dosage Increases: Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL. As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a subtherapeutic serum concentration measurement should be conservative. In general, limiting infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI). PRECAUTIONS General: Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy and prior to increases in theophylline dose (see WARNINGS). Monitoring Serum Theophylline Concentrations: page 6 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows: 1. Before making a dose increase to determine whether the serum concentration is subtherapeutic in a patient who continues to be symptomatic. 2. Whenever signs or symptoms of theophylline toxicity are present. 3. Whenever there is a new illness, worsening of an existing concurrent illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued). In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is <10 mcg/mL indicating the need for an additional loading dose, or >20 mcg/mL indicating the need to delay starting the constant IV infusion. Once the infusion is begun, a second measurement should be obtained after one expected half life (e.g., approximately 4 hours in pediatric patients age 1 to 9 years and 8 hours in nonsmoking adults; See Table I for the expected half life in additional patient populations). The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or subtherapeutic theophylline concentration from being achieved. If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is ≥10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated (see DOSAGE AND ADMINISTRATION for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half life after starting the constant infusion to determine the direction in which the serum concentration has changed. Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion. The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels. When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL. Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques. Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 µEq/l to 800 µEq/l), total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients. Drug Interactions: Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady- state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially page 7 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance). The listing of drugs in Tables II and III are current as of September 1, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported. Table II. Clinically significant drug interactions with theophylline* Drug Type of Interaction Effect** Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. page 8 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic May lower theophylline seizure threshold. Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non- depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital. page 9 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%. Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase * Refer to PRECAUTIONS, Drug Interactions for further information regarding table. ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.* albuterol, lomefloxacin systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, methylprednisolone with or without sulbactam metronidazole atenolol metoprolol page 10 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda azithromycin nadolol caffeine, nifedipine dietary ingestion nizatidine cefaclor norfloxacin co-trimoxazole ofloxacin (trimethoprim and omeprazole sulfamethoxazole) prednisone, prednisolone diltiazem ranitidine dirithromycin rifabutin enflurane roxithromycin famotidine sorbitol felodipine (purgative doses do not finasteride inhibit theophylline hydrocortisone absorption) isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide * Refer to PRECAUTIONS, Drug Interactions for information regarding table. The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long term carcinogenicity studies have been carried out in mice (oral doses 30 - 150 mg/kg) and rats (oral doses 5 - 75 mg/kg). Results are pending. Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic. In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1 - 3 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was page 11 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administered to F344 rats and B6C3F1 mice at oral doses of 40 - 300 mg/kg (approximately 2 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight. Pregnancy Category C: Teratogenic Effects There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, maternal doses of theophylline less than one to two times the recommended oral dose in humans caused fetal harm, including fetal malformations. Asthma is a serious and potentially life-threatening condition. Poorly controlled asthma during pregnancy is associated with adverse outcomes for mother and fetus. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Population-based studies and post-marketing adverse event reporting of theophylline used during human pregnancy have not demonstrated an increased risk of major congenital anomalies. However, most studies were not large enough to detect a less than two fold increase in risk for congenital anomalies. Post-marketing data are reported voluntarily and do not always reliably estimate the frequency of particular adverse outcomes. In animal reproduction studies, theophylline produced teratogenic effects when pregnant mice, rats and rabbits were dosed during the period of organogenesis. In mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis) produced a cleft palate and digital abnormalities. Micromelia, micrognathia, club foot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis. In rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality occurred at a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis). In rabbits dosed intravenously throughout organogenesis with 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), caused cleft palate and was embryolethal. This dose was maternally toxic as one doe died and clinical signs of toxicity occurred in others. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations. Nursing Mothers: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations. Pediatric Use: Theophylline is safe and effective for the approved indications in pediatric patients (see INDICATIONS AND USAGE). The constant infusion rate of intravenous theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of theophylline metabolic pathways in children under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group. Geriatric Use: Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline infusion rate. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum infusion rate of theophylline in patients greater than 60 years of age ordinarily should not exceed 17 mg/hr. unless the patient continues to be symptomatic and the steady state serum theophylline concentration is < 10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theophylline infusion rates greater than 17 mg/hr. should be prescribed with caution in elderly patients. ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when serum theophylline concentrations are < 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE). page 12 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other adverse reactions that have been reported at serum theophylline concentrations < 20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥ 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations < 20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations < 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations < 20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Table IV. Manifestations of theophylline toxicity.* Percentage of patients reported with sign or symptom Acute Overdose Chronic Overdosage (Large Single Ingestion) (Multiple Excessive Doses) Study 1 Study 2 Study 1 Study 2 Sign/Symptom (n=157) (n=14) (n=92) (n=102) Asymptomatic NR 0 NR 6 Gastrointestinal Vomiting 73 93 30 61 Abdominal Pain NR 21 NR 12 Diarrhea NR 0 NR 14 Hematemesis NR 0 NR 2 Metabolic/Other Hypokalemia 85 79 44 43 Hyperglycemia 98 NR 18 NR Acid/base disturbance 34 21 9 5 Rhabdomyolysis NR 7 NR 0 Cardiovascular Sinus tachycardia 100 86 100 62 Other supraventricular 2 21 12 14 page 13 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda tachycardias Ventricular premature beats 3 21 10 19 Atrial fibrillation or flutter 1 NR 12 NR Multifocal atrial tachycardia 0 NR 2 NR Ventricular arrhythmias with 7 14 40 0 hemodynamic instability Hypotension/shock NR 21 NR 8 Neurologic Nervousness NR 64 NR 21 Tremors 38 29 16 14 Disorientation NR 7 NR 11 Seizures 5 14 14 5 Death 3 21 10 4 * These data are derived from two studies in patients with serum theophylline concentrations > 30 mcg/mL. In the first study (Study #1 - Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 - Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. ** NR = Not reported in a comparable manner. OVERDOSAGE General: The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: 1) acute overdose, i.e., infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and 2) chronic overdosage, i.e., excessive maintenance infusion rate for greater than 24 hours. The most common causes of chronic theophylline overdosage include clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe. Several studies have described the clinical manifestations of theophylline overdose following oral administration and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is > 100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations > 30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients > 60 years are at the greatest risk for severe toxicity and page 14 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. The frequency of various reported manifestations of oral theophylline overdose according to the mode of overdose are listed in Table IV. Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. Seizures associated with serum theophylline concentrations > 30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. Overdose Management: General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations > 30 mcg/mL While Receiving Intravenous Theophylline 1. Stop the theophylline infusion. 2. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. 3. Institute supportive care, including establishment of intravenous access, maintenance of the airway and electrocardiographic monitoring. 4. Treatment of Seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1 - 0.2 mg/kg every 1 - 3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30 - 60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain. 5. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations > 100 mcg/mL or chronic overdosage in patients > 60 years of age with serum theophylline concentrations > 30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline- induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous Phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD. 6. Treatment of Cardiac Arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life- threatening arrhythmias. They do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia. page 15 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7. Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline concentrations should be continued until it is clear that the concentration is no longer rising and has returned to nontoxic levels. 8. General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. 9. Enhance Clearance of Theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young pediatric patients and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal). Specific Recommendations: Acute Overdose (e.g., excessive loading dose or excessive infusion rate for <24 hours) A. Serum Concentration > 20 < 30 mcg/mL 1. Stop the theophylline infusion. 2. Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to insure that the concentration is decreasing. B. Serum Concentration > 30 < 100 mcg/mL 1. Stop the theophylline infusion. 2. Administer multiple dose oral activated charcoal and measures to control emesis. 3. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 4. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). C. Serum Concentration > 100 mcg/mL 1. Stop the theophylline infusion. 2. Consider prophylactic anticonvulsant therapy. 3. Administer multiple-dose oral activated charcoal and measures to control emesis. 4. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). 5. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. page 16 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Chronic Overdosage (e.g., excessive infusion rate for greater than 24 hours) A. Serum Concentration > 20 < 30 mcg/mL (with manifestations of theophylline toxicity) 1. Stop the theophylline infusion. 2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is decreasing. B. Serum Concentration >30 mcg/mL in patients <60 years of age 1. Stop the theophylline infusion. 2. Administer multiple-dose oral activated charcoal and measures to control emesis. 3. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 4. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). C. Serum Concentration >30 mcg/mL in patients ≥60 years of age 1. Stop the theophylline infusion. 2. Consider prophylactic anticonvulsant therapy. 3. Administer multiple-dose oral activated charcoal and measures to control emesis. 4. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). 5. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Extracorporeal Removal: Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5 - 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective. DOSAGE AND ADMINISTRATION General Considerations: The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either subtherapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses: page 17 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda C = LD/V If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows: D = (Desired C − Measured C) (V) where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours. A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in nonsmoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/ mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average pediatric patient (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/ kg/hr. Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults: See Table I for the expected half life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course. In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Initial theophylline infusion rates following an appropriate loading dose. Patient population Age Theophylline infusion rate (mg/kg/hr)* † Neonates Infants Postnatal age up to 24 days Postnatal age beyond 24 days 6-52 weeks old 1 mg/kg q12h/‡ 1.5 mg/kg q12h/‡ mg/kg/hr = (0.008)(age in weeks) + 0.21 page 18 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Young pediatric patients 1-9 years 0.8 Older pediatric patients 9-12 years 0.7 Adolescents (cigarette or marijuana smokers) 12-16 years 0.7 Adolescents (nonsmokers) 12-16 years 0.5 § Adults (otherwise healthy nonsmokers) 16-60 years 0.4 § Elderly >60 years 0.3 ¶ Cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multi-organ failure, or shock 0.2 ¶ * To achieve a target concentration of 10 mcg/mL. Aminophylline = theophylline/0.8. Use ideal body weight for obese patients. † Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine). ‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea. § Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose. ¶ Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose. Table VI. Final dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶ 20-24.9 mcg/mL Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. 25-30 mcg/mL Stop infusion for 12 hours in pediatric patients and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see recommendations for chronic overdosage). >30 mcg/mL Stop the infusion and treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is page 19 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. ¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS). Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open flow control clamp and clear air from set. Close clamp. 7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. 8. Regulate rate of administration with flow control clamp. WARNING: DO NOT USE FLEXIBLE CONTAINER IN SERIES CONNECTIONS. HOW SUPPLIED Theophylline 200, 400 and 800 mg in 5% Dextrose Injection, USP is supplied in single-dose containers in various sizes and concentrations as shown in the accompanying Table. NDC No. Product Theophyllin per 100 mL e Dextrose per 100 mL Theophyllin per mL e pH (range) mOsmol/ L (calc) 50 mL 100 mL Size 250 mL 500 mL 1000 mL 0409-7665-0T9heophyllin 800 mg in 5% Dextrose Inj., USP e 80 mg 5 g 0.8 mg 4.3 (3.5–6.5) 257 X 0409-7665-0T3heophyllin 400mg in 5% Dextrose Inj., USP e 80 mg 5 g 0.8 mg 4.3 (3.5–6.5) 257 X 0409-7666-0T3heophyllin 800 mg in 5% Dextrose Inj., USP e 160 mg 5 g 1.6 mg 4.3 (3.5–6.5) 261 X 0409-7666-6T2heophyllin 400 mg e 160 mg 5 g 1.6 mg 4.3 (3.5–6.5) 261 X page 20 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda in 5% Dextrose Inj., USP 0409-7668-2T3heophyllin 200 mg in 5% Dextrose Inj., USP e 200 mg 5 g 2 mg 4.3 (3.5–6.5) 263 X 0409-7705-6T2heophyllin 800 mg in 5% Dextrose Inj., USP e 320 mg 5 g 3.2 mg 4.3 (3.5–6.5) 270 X 0409-7677-1T3heophyllin 200 mg in 5% Dextrose Inj., USP e 400 mg 5 g 4 mg 4.3 (3.5–6.5) 275 X Protect from freezing. Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.] Revised: March, 2008 Printed in USA EN-1761 Hospira, Inc., Lake Forest, IL 60045 USA page 21 of 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:17.591906	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019211s040lbl.pdf', 'application_number': 19211, 'submission_type': 'SUPPL ', 'submission_number': 40}
11,452	---------- THEOPHYLLINE IN DEXTROSE - theophylline injection, solution Hospira, Inc. THEOPHYLLINE 200, 400 AND 800 mg in 5% Dextrose Injection, USP Flexible Plastic Container Do not admix with other drugs Rx only DESCRIPTION Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula: Chemical Structure The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17. Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose sugar freely soluble in water. It has the following structural formula: Chemical Structure The molecular weight is 198.17. Water for Injection, USP is chemically designated H2O. Theophylline 200, 400 and 800 mg in 5% Dextrose Injection, USP are sterile, nonpyrogenic solutions of theophylline, anhydrous and dextrose in water for injection. See Table in HOW SUPPLIED for summary of contents and characteristics of these solutions. The solutions contain no bacteriostatic, antimicrobial agent or added buffer and are intended only for use as a single-dose administration. When smaller doses are required, the unused portion should be discarded. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain of its chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period. CLINICAL PHARMACOLOGY Mechanism of Action: page 1 of 21 Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV), while nonbronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. Serum Concentration-Effect Relationship: Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control and pulmonary function has been found in most studies to require serum theophylline concentrations >10 mcg/ mL. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining the average serum theophylline concentration between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events. Pharmacokinetics: Overview The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within- subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients receiving intravenous theophylline (e.g., at 24-hr intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Effects on Laboratory Tests). Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.¶ Population characteristics Total body clearance* mean (range)†† (mL/kg/min) Half-life mean (range)†† (hr) Age Premature neonates postnatal age 3-15 days postnatal age 25-57 days 0.29 (0.09-0.49) 0.64 (0.04-1.2) 30 (17-43) 20 (9.4-30.6) Term infants postnatal age 1-2 days postnatal age 3-30 weeks NR† NR† 25.7 (25-26.5) 11 (6-29) Pediatric patients 1-4 years 4-12 years 13-15 years 16-17 years 1.7 (0.5-2.9) 1.6 (0.8-2.4) 0.9 (0.48-1.3) 1.4 (0.2-2.6) 3.4 (1.2-5.6) NR† NR† 3.7 (1.5-5.9) Adults (16-60 years) otherwise healthy nonsmoking asthmatics 0.65 (0.27-1.03) 8.7 (6.1-12.8) Elderly (>60 years) nonsmokers with normal cardiac, liver, and renal function 0.41 (0.21-0.61) 9.8 (1.6-18) page 2 of 21 Concurrent illness or altered physiological state Acute pulmonary edema 0.33 (0.07-2.45) 19 (3.1-8.2) COPD- >60 years, stable nonsmoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6) COPD with cor pulmonale 0.48 (0.08-0.88) NR† Cystic fibrosis (14-28 years) 1.25 (0.31-2.2) 6.0 (1.8-10.2) Fever associated with acute viral respiratory illness (pediatric patients 9-15 years) NR† 7.0 (1.0-13) Liver disease- cirrhosis acute hepatitis cholestasis 0.31 (0.1-0.7) 0.35 (0.25-0.45) 0.65 (0.25-1.45) 32 (10-56) 19.2 (16.6-21.8) 14.4 (5.7-31.8) Pregnancy- 1st trimester 2nd trimester 3rd trimester NR† NR† NR† 8.5 (3.1-13.9) 8.8 (3.8-13.8) 13.0 (8.4-17.6) Sepsis with multi-organ failure 0.47 (0.19-1.9) 18.8 (6.3-24.1) Thyroid disease- hypothyroid hyperthyroid 0.38 (0.13-0.57) 0.8 (0.68-0.97) 11.6 (8.2-25) 4.5 (3.7-5.6) ¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples. * Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations < 20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics. †† Reported range or estimated range (mean ±2 SD) where actual range not reported. † NR = not reported or not reported in a comparable format. ** Median Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline. Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding page 3 of 21 may have a subtherapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL. Metabolism In adults and pediatric patients beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3 dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, nonlinearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this nonlinearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes. Excretion In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and pediatric patients >3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (see WARNINGS). Serum Concentrations at Steady State In a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. In nonsmoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average pediatric patient (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/kg/hr. (See DOSAGE AND ADMINISTRATION.) Special Populations (see Table I for mean clearance and half-life values) Geriatrics The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS). Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION). Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy. Race Pharmacokinetic differences in theophylline clearance due to race have not been studied. Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end- stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, page 4 of 21 approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS). Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS). Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS). Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to nonsmoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance. Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS). Miscellaneous Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis. CLINICAL STUDIES: Inhaled beta-2 selective agonists and systemically administered corticosteroids are the treatments of first choice for management of acute exacerbations of asthma. The results of controlled clinical trials on the efficacy of adding intravenous theophylline to inhaled beta-2 selective agonists and systemically administered corticosteroids in the management of acute exacerbations of asthma have been conflicting. Most studies in patients treated for acute asthma exacerbations in an emergency department have shown that addition of intravenous theophylline does not produce greater bronchodilation and increases the risk of adverse effects. In contrast, other studies have shown that addition of intravenous theophylline is beneficial in the treatment of acute asthma exacerbations in patients requiring hospitalization, particularly in patients who are not responding adequately to inhaled beta-2 selective agonists. In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements. INDICATIONS AND USAGE Theophylline in 5% Dextrose Injection USP is indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis. CONTRAINDICATIONS Theophylline in 5% Dextrose Injection USP is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. WARNINGS Concurrent Illness: Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance: There are several readily identifiable causes of reduced theophylline clearance. If the infusion rate is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be page 5 of 21 given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Pediatric patients <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants < 3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin) (see PRECAUTIONS, Drug Interactions, Table II). When Signs or Symptoms of Theophylline Toxicity Are Present: Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately. Dosage Increases: Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL. As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a subtherapeutic serum concentration measurement should be conservative. In general, limiting infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI). Solutions containing dextrose without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration of erythrocytes. The intravenous administration of these solutions may cause fluid overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. Because dosages of these drugs are titrated to response (see DOSAGE AND ADMINISTRATION), no additives should be made to Theophylline in 5% Dextrose Injection USP. page 6 of 21 PRECAUTIONS General: Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy and prior to increases in theophylline dose (see WARNINGS). Monitoring Serum Theophylline Concentrations: Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows: 1. Before making a dose increase to determine whether the serum concentration is subtherapeutic in a patient who continues to be symptomatic. 2. Whenever signs or symptoms of theophylline toxicity are present. 3. Whenever there is a new illness, worsening of an existing concurrent illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued). In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is <10 mcg/mL indicating the need for an additional loading dose, or >20 mcg/mL indicating the need to delay starting the constant IV infusion. Once the infusion has begun, a second measurement should be obtained after one expected half life (e.g., approximately 4 hours in pediatric patients age 1 to 9 years and 8 hours in nonsmoking adults; See Table I for the expected half life in additional patient populations). The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or subtherapeutic theophylline concentration from being achieved. If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is ≥ 10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated (see DOSAGE AND ADMINISTRATION for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half-life after starting the constant infusion to determine the direction in which the serum concentration has changed. Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion. The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels. When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL. Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged therapy or whenever the condition of the patient warrants such evaluation. Do not use plastic container in series connection. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. These solutions are intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours. Use only if solution is clear and container and seals are intact. Effects on Laboratory Tests: As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L), total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, page 7 of 21 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients. Drug Interactions: Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady- state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance). The listing of drugs in Tables II and III are current as of September 1, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported. Table II. Clinically significant drug interactions with theophylline. Drug Type of Interaction Effect* Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without page 8 of 21 reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic May lower theophylline seizure threshold. Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Similar to diazepam. page 9 of 21 Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non- depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital Similar to aminoglutethimide. 25% decrease after two weeks of concurrent Phenobarbital. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%. Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20-40% decrease Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33-100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase * Refer to PRECAUTIONS, Drug Interactions for further information regarding table. ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. page 10 of 21 Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.* albuterol, lomefloxacin systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, methylprednisolone with or without sulbactam metronidazole atenolol metoprolol azithromycin nadolol caffeine, nifedipine dietary ingestion nizatidine cefaclor norfloxacin co-trimoxazole ofloxacin (trimethoprim and omeprazole sulfamethoxazole) prednisone, prednisolone diltiazem ranitidine dirithromycin rifabutin enflurane roxithromycin famotidine sorbitol felodipine (purgative doses do not finasteride inhibit theophylline hydrocortisone absorption) isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide * Refer to PRECAUTIONS, Drug Interactions for information regarding table. The Effect of Other Drugs on Theophylline Serum Concentration Measurements: page 11 of 21 Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long term carcinogenicity studies have been carried out in mice (oral doses 30 - 150 mg/kg) and rats (oral doses 5 - 75 mg/kg). Results are pending. Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic. In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1 - 3 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40 - 300 mg/kg (approximately 2 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight. Pregnancy Category C: Teratogenic Effects There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, maternal doses of theophylline less than one to two times the recommended oral dose in humans caused fetal harm, including fetal malformations. Asthma is a serious and potentially life-threatening condition. Poorly controlled asthma during pregnancy is associated with adverse outcomes for mother and fetus. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Population-based studies and post-marketing adverse event reporting of theophylline used during human pregnancy have not demonstrated an increased risk of major congenital anomalies. However, most studies were not large enough to detect a less than two fold increase in risk for congenital anomalies. Post-marketing data are reported voluntarily and do not always reliably estimate the frequency of particular adverse outcomes. In animal reproduction studies, theophylline produced teratogenic effects when pregnant mice, rats and rabbits were dosed during the period of organogenesis. In mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m2 basis) produced a cleft palate and digital abnormalities. Micromelia, micrognathia, club foot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis. In rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis) produced digital abnormalities. Embryolethality occurred at a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis). In rabbits dosed intravenously throughout organogenesis with 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m2 basis), caused cleft palate and was embryolethal. This dose was maternally toxic as one doe died and clinical signs of toxicity occurred in others. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m2 basis) increased the incidence of skeletal variations. Nursing Mothers: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations. Pediatric Use: Theophylline is safe and effective for the approved indications in pediatric patients (see INDICATIONS AND USAGE). The constant infusion rate of intravenous theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of theophylline metabolic pathways in children under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group. Geriatric Use: Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater page 12 of 21 than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline infusion rate. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum infusion rate of theophylline in patients greater than 60 years of age ordinarily should not exceed 17 mg/hr unless the patient continues to be symptomatic and the steady state serum theophylline concentration is < 10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theophylline infusion rates greater than 17 mg/hr should be prescribed with caution in elderly patients. ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when serum theophylline concentrations are < 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE). Other adverse reactions that have been reported at serum theophylline concentrations < 20 mcg/mL include diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥ 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations < 20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations < 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations < 20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations (see OVERDOSAGE). Table IV. Manifestations of theophylline toxicity.* Percentage of patients reported with sign or symptom Acute Overdose Chronic Overdosage (Large Single Ingestion) (Multiple Excessive Doses) Study 1 Study 2 Study 1 Study 2 Sign/Symptom (n=157) (n=14) (n=92) (n=102) Asymptomatic NR 0 NR 6 Gastrointestinal Vomiting 73 93 30 61 Abdominal Pain NR 21 NR 12 Diarrhea NR 0 NR 14 Hematemesis NR 0 NR 2 Metabolic/Other Hypokalemia 85 79 44 43 page 13 of 21 Hyperglycemia 98 NR 18 NR Acid/base disturbance 34 21 9 5 Rhabdomyolysis NR 7 NR 0 Cardiovascular Sinus tachycardia 100 86 100 62 Other supraventricular 2 21 12 14 tachycardias Ventricular premature beats 3 21 10 19 Atrial fibrillation or flutter 1 NR 12 NR Multifocal atrial tachycardia 0 NR 2 NR Ventricular arrhythmias with 7 14 40 0 hemodynamic instability Hypotension/shock NR 21 NR 8 Neurologic Nervousness NR 64 NR 21 Tremors 38 29 16 14 Disorientation NR 7 NR 11 Seizures 5 14 14 5 Death 3 21 10 4 * These data are derived from two studies in patients with serum theophylline concentrations > 30 mcg/mL. In the first study (Study #1 - Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 - Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations >30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. ** NR = Not reported in a comparable manner. page 14 of 21 Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. OVERDOSAGE General: The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: 1) acute overdose, i.e., infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and 2) chronic overdosage, i.e., excessive maintenance infusion rate for greater than 24 hours. The most common causes of chronic theophylline overdosage include clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe. Several studies have described the clinical manifestations of theophylline overdose following oral administration and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is > 100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations > 30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients > 60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. The frequency of various reported manifestations of oral theophylline overdose according to the mode of overdose are listed in Table IV. Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations. Seizures associated with serum theophylline concentrations > 30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. Overdose Management: General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations > 30 mcg/mL While Receiving Intravenous Theophylline 1. Stop the theophylline infusion. 2. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. 3. Institute supportive care, including establishment of intravenous access, maintenance of the airway and electrocardiographic monitoring. 4. Treatment of Seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1 - 0.2 mg/kg every 1 - 3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30 - 60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain. 5. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations > 100 mcg/mL or chronic overdosage in patients > 60 years of age with serum theophylline concentrations > 30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline- page 15 of 21 induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD. 6. Treatment of Cardiac Arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias. They do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia. 7. Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline concentrations should be continued until it is clear that the concentration is no longer rising and has returned to nontoxic levels. 8. General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. 9. Enhance Clearance of Theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young pediatric patients and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal). Specific Recommendations: Acute Overdose (e.g., excessive loading dose or excessive infusion rate for <24 hours) A. Serum Concentration > 20 < 30 mcg/mL 1. Stop the theophylline infusion. 2. Monitor the patient and obtain a serum theophylline concentration in 2 - 4 hours to ensure that the concentration is decreasing. B. Serum Concentration > 30 < 100 mcg/mL 1. Stop the theophylline infusion. 2. Administer multiple dose oral activated charcoal and measures to control emesis. 3. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 4. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). page 16 of 21 C. Serum Concentration > 100 mcg/mL 1. Stop the theophylline infusion. 2. Consider prophylactic anticonvulsant therapy. 3. Administer multiple-dose oral activated charcoal and measures to control emesis. 4. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). 5. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Chronic Overdosage (e.g., excessive infusion rate for greater than 24 hours) A. Serum Concentration > 20 < 30 mcg/mL (with manifestations of theophylline toxicity) 1. Stop the theophylline infusion. 2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to ensure that the concentration is decreasing. B. Serum Concentration >30 mcg/mL in patients <60 years of age 1. Stop the theophylline infusion. 2. Administer multiple-dose oral activated charcoal and measures to control emesis. 3. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. 4. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal). C. Serum Concentration >30 mcg/mL in patients ≥60 years of age 1. Stop the theophylline infusion. 2. Consider prophylactic anticonvulsant therapy. 3. Administer multiple-dose oral activated charcoal and measures to control emesis. 4. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal). 5. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Extracorporeal Removal: Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5 - 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective. page 17 of 21 DOSAGE AND ADMINISTRATION These solutions are for intravenous use only. General Considerations: The steady-state serum theophylline concentration is a function of the infusion rate and the rate of theophylline clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance. For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either subtherapeutic or potentially toxic serum theophylline concentrations in individual patients. The dose of theophylline must be individualized on the basis of serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. When theophylline is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses: C = LD/V If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of theophylline administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum theophylline concentration. Therefore, in a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received theophylline, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows: D = (Desired C − Measured C) (V) where D is the loading dose, C is the serum theophylline concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum theophylline concentration if the patient has received any theophylline in the previous 24 hours. A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in nonsmoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/ mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average pediatric patient (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/ kg/hr. Since there is large interpatient variability in theophylline clearance, serum concentrations will rise or fall when the patient’s clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults: See Table I for the expected half life in additional patient populations) to determine if the concentration is accumulating or declining from the post loading dose level. If the level is declining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient’s course. In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those taking drugs that markedly reduce theophylline clearance (e.g., cimetidine), the initial theophylline infusion rate should not exceed 17 mg/hr unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains initial theophylline infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit page 18 of 21 for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Initial theophylline infusion rates following an appropriate loading dose. Patient population Age Theophylline infusion rate (mg/kg/hr)* † Neonates Postnatal age up to 24 days 1 mg/kg q12h/‡ Postnatal age beyond 24 days 1.5 mg/kg q12h/‡ Infants 6-52 weeks old mg/kg/hr = (0.008)(age in weeks) + 0.21 Young pediatric patients 1-9 years 0.8 Older pediatric patients 9-12 years 0.7 Adolescents (cigarette or marijuana 12-16 years 0.7 smokers) Adolescents (nonsmokers) 12-16 years 0.5 § Adults (otherwise healthy nonsmokers) 16-60 years 0.4 § Elderly >60 years 0.3 ¶ Cardiac decompensation, cor pulmonale, 0.2 ¶ liver dysfunction, sepsis with multi-organ failure, or shock * To achieve a target concentration of 10 mcg/mL. Aminophylline = theophylline/0.8. Use ideal body weight for obese patients. † Lower initial dosage may be required for patients receiving other drugs that decrease theophylline clearance (e.g., cimetidine). ‡ To achieve a target concentration of 7.5 mcg/mL for neonatal apnea. § Not to exceed 900 mg/day, unless serum levels indicate the need for a larger dose. ¶ Not to exceed 400 mg/day, unless serum levels indicate the need for a larger dose. Table VI. Final dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase infusion rate about 25%. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck serum concentration at 24 hour intervals.¶ If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in infusion rate to provide greater margin of safety even if current dosage is tolerated.¶ page 19 of 21 20-24.9 mcg/mL Decrease infusion rate by 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. 25-30 mcg/mL Stop infusion for 12 hours in pediatric patients and 24 hours in adults and decrease subsequent infusion rate at least 25% even if no adverse effects are present. Recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated (see recommendations for chronic overdosage). >30 mcg/mL Stop the infusion and treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease infusion rate by at least 50% and recheck serum concentration after 12 hours in pediatric patients and 24 hours in adults to guide further dosage adjustment. ¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open flow control clamp and clear air from set. Close clamp. 7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. 8. Regulate rate of administration with flow control clamp. WARNING: DO NOT USE FLEXIBLE CONTAINER IN SERIES CONNECTIONS. HOW SUPPLIED Theophylline 200, 400 and 800 mg in 5% Dextrose Injection, USP is supplied in single-dose containers in various sizes and concentrations as shown in the accompanying Table. NDC No. Product Theophylline per 100 mL Dextrose per 100 mL Theophylline per mL pH (range) mOsmol/L (calc) 50 mL Size 100 mL 250 mL 0409-7666-62Theophylline 400 mg in 5% 160 mg 5 g 1.6 mg 4.3 (3.5–6.5) 261 X page 20 of 21 Dextrose Inj., USP 0409-7668-23Theophylline 200 mg in 5% Dextrose Inj., USP 200 mg 5 g 2 mg 4.3 (3.5–6.5) 263 X 0409-7705-62Theophylline 800 mg in 5% Dextrose Inj., USP 320 mg 5 g 3.2 mg 4.3 (3.5–6.5) 270 X 0409-7677-13Theophylline 200 mg in 5% Dextrose Inj., USP 400 mg 5 g 4 mg 4.3 (3.5–6.5) 275 X Protect from freezing. Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.] Revised: July, 2008 Printed in USA EN-1839 Hospira, Inc., Lake Forest, IL 60045 USA page 21 of 21	custom-source	2025-02-12T13:45:17.674400	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019211s042lbl.pdf', 'application_number': 19211, 'submission_type': 'SUPPL ', 'submission_number': 42}
11,455		custom-source	2025-02-12T13:45:17.810426	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/18-998S058_Vasotec_prntlbl.pdf', 'application_number': 19221, 'submission_type': 'SUPPL ', 'submission_number': 26}
11,456	TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 1 of 27 TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) Rx Only USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASERETIC should be discontinued as soon as possible. (See WARNINGS, Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality). DESCRIPTION VASERETIC® (Enalapril Maleate-Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1 [N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is: structural formula Enalapril maleate is a white to off-white crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Reference ID: 2916973 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 2 of 27 Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1 dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is: structural formula It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. VASERETIC is available in the tablet combination of enalapril maleate with hydrochlorothiazide: VASERETIC 10-25, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide. Inactive ingredients are: iron oxide, lactose, magnesium stearate, sodium bicarbonate, and starch. CLINICAL PHARMACOLOGY As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of enalapril maleate blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic. In clinical studies, the extent of blood pressure reduction seen with the combination of enalapril maleate and hydrochlorothiazide was approximately additive. The antihypertensive effect of VASERETIC was usually sustained for at least 24 hours. Concomitant administration of enalapril maleate and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities. Enalapril Maleate Reference ID: 2916973 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 3 of 27 Mechanism of Action: Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin- converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril remains to be elucidated. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril maleate monotherapy than non-black patients. In contrast, hydrochlorothiazide was more effective in black patients than enalapril. Concomitant administration of enalapril maleate and hydrochlorothiazide was equally effective in black and non-black patients. Pharmacokinetics and Metabolism: Following oral administration of enalapril maleate, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Reference ID: 2916973 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 4 of 27 Excretion of enalaprilat and enalapril is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤ 30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at the rate of 62 mL/min. Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. Pharmacodynamics: Administration of enalapril maleate to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is infrequent with enalapril alone but it can be anticipated in volume-depleted patients, such as patients treated with diuretics. In clinical trials with enalapril and hydrochlorothiazide administered concurrently, syncope occurred in 1.3 percent of patients (see WARNINGS and DOSAGE AND ADMINISTRATION). Reference ID: 2916973 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 5 of 27 In most patients studied, after oral administration of a single dose of enalapril maleate, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. At recommended doses, antihypertensive effects of enalapril maleate monotherapy have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval; this was less frequently observed with concomitant administration of enalapril maleate and hydrochlorothiazide. Achievement of optimal blood pressure reduction may require several weeks of enalapril therapy in some patients. The antihypertensive effects of enalapril have continued during long-term therapy. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In hemodynamic studies in patients with essential hypertension, blood pressure reduction produced by enalapril was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate (see PRECAUTIONS, Drug Interactions, Enalapril Maleate). Hydrochlorothiazide The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours. Reference ID: 2916973 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 6 of 27 Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier. INDICATIONS AND USAGE VASERETIC is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial treatment (see DOSAGE AND ADMINISTRATION). In using VASERETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril does not have a similar risk (see WARNINGS). In considering use of VASERETIC, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non- blacks (see WARNINGS, Head and Neck Angioedema). CONTRAINDICATIONS VASERETIC is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. WARNINGS General Reference ID: 2916973 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 7 of 27 Enalapril Maleate Hypotension: Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons such as those treated vigorously with diuretics or patients on dialysis. Syncope has been reported in 1.3 percent of patients receiving VASERETIC. In patients receiving enalapril alone, the incidence of syncope is 0.5 percent. The overall incidence of syncope may be reduced by proper titration of the individual components (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which usually can be given without difficulty once the blood pressure has increased after volume expansion. Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including VASERETIC) may be subject to a variety of adverse reactions, some of them serious. Reference ID: 2916973 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 8 of 27 Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases VASERETIC should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an Reference ID: 2916973 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 9 of 27 ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low- density lipoprotein apheresis with dextran sulfate absorption. Neutropenia/Agranulocytosis: Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hydrochlorothiazide Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. Reference ID: 2916973 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 10 of 27 Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Enalapril Maleate and Hydrochlorothiazide). Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Pregnancy Enalapril-Hydrochlorothiazide There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of hydrochlorothiazide. These doses of enalapril are 4.3 and 26 times (mice and rats, respectively) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m2); the dose of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD. At these doses, fetotoxicity expressed as a decrease in average fetal weight occurred in both species. No fetotoxicity occurred at lower doses; 30/10 mg/kg/day of enalapril-hydrochlorothiazide in rats and 10/10 mg/kg/day of enalapril-hydrochlorothiazide in mice. When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASERETIC should be discontinued as soon as possible (see Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality, below). Reference ID: 2916973 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 11 of 27 Enalapril Maleate Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of VASERETIC as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. Reference ID: 2916973 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 12 of 27 If oligohydramnios is observed, VASERETIC should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the MRHDD. Hydrochlorothiazide Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults. PRECAUTIONS General Enalapril Maleate Reference ID: 2916973 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 13 of 27 Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldersterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials treated with enalapril alone. In most cases these were isolated values which resolved despite continued therapy, although hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Hyperkalemia was less frequent (approximately 0.1 percent) in patients treated with enalapril plus hydrochlorothiazide. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of Reference ID: 2916973 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 14 of 27 potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hydrochlorothiazide Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Because enalapril reduces the production of aldosterone, concomitant therapy with enalapril attenuates the diuretic-induced potassium loss (see Drug Interactions, Agents Increasing Serum Potassium). Reference ID: 2916973 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 15 of 27 Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy. The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should Reference ID: 2916973 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 16 of 27 be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors. These patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with VASERETIC is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Enalapril Maleate Hypotension – Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or Reference ID: 2916973 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 17 of 27 increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Other Cardiovascular Agents: Enalapril has been used concomitantly with beta adrenergic- blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions. Agents Increasing Serium Potassium: Enalapril attenuates diuretic-induced potassium loss. Potassium-sparing diuretics (e.g., spironolactone, triameterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were Reference ID: 2916973 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 18 of 27 reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VASERETIC. Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics – potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) – dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs – additive effect or potentiation. Cholestyramine and colestipol resins – Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) – possible increased responsiveness to the muscle relaxant. Reference ID: 2916973 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 19 of 27 Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with VASERETIC. Non-steroidal Anti-inflammatory Drugs – In some patients, the administration of a non steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when VASERETIC and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Carcinogenesis, Mutagenesis, Impairment of Fertility Enalapril in combination with hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril-hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution assay in rat hepatocytes or chromosomal aberrations in an in vivo mouse bone marrow assay. Enalapril Maleate There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. Reference ID: 2916973 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 20 of 27 There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Hydrochlorothiazide Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in male and female rats at doses up to approximately 100 mg/kg/day (18 times the MRHDD when compared on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively, the MRHDD when compared on a body surface area basis. Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality). Reference ID: 2916973 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 21 of 27 Nursing Mothers Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Because of the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of VASERETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS VASERETIC has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with VASERETIC no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide. Reference ID: 2916973 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 22 of 27 The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with VASERETIC in controlled clinical trials are shown below. Percent of Patients Deleted: ¶ in Controlled Studies VASERETIC (n=1580) Placebo Incidence (n=230) (discontinuation) Incidence Dizziness 8.6 (0.7) 4.3 Headache 5.5 (0.4) 9.1 Fatigue 3.9 (0.8) 2.6 Cough 3.5 (0.4) 0.9 Muscle Cramps 2.7 (0.2) 0.9 Nausea 2.5 (0.4) 1.7 Asthenia 2.4 (0.3) 0.9 Orthostatic Effects 2.3 (<0.1) 0.0 Impotence 2.2 (0.5) 0.5 Diarrhea 2.1 (<0.1) 1.7 Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain; Cardiovascular: Orthostatic hypotension, palpitation, tachycardia; Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth; Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo; Skin: Pruritus, rash; Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection. Angioedema: Angioedema has been reported in patients receiving VASERETIC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx 22 Reference ID: 2916973 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 23 of 27 occurs, treatment with VASERETIC should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients (see WARNINGS). Cough: See PRECAUTIONS, Cough. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6 percent of patients with essential hypertension treated with VASERETIC. More marked increases have been reported in other enalapril experience. Increases are more likely to occur in patients with renal artery stenosis (see PRECAUTIONS). Serum Uric Acid, Glucose, Magnesium, and Calcium: See PRECAUTIONS. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with VASERETIC but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity. Enalapril Maleate – Enalapril has been evaluated for safety in more than 10,000 patients. In clinical trials adverse reactions which occurred with enalapril were also seen with VASERETIC. However, since enalapril has been marketed, the following adverse reactions Reference ID: 2916973 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 24 of 27 have been reported: Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid reactions during membrane exposure); Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; hypotension; angina pectoris, Raynaud’s phenomenon; Digestive: lleus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis, dry mouth; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Nervous System/Psychiatric: Depression, confusion, ataxia, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality; Urogenital: Renal failure, oliguria, renal dysfunction, (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia; Respiratory: Pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection; Skin: Exfoliative dermatitits, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, tearing. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality. Hydrochlorothiazide – Body as a Whole: Weakness; Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia; Reference ID: 2916973 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 25 of 27 Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: Transient blurred vision, xanthopsia. OVERDOSAGE No specific information is available on the treatment of overdosage with VASERETIC. Treatment is symptomatic and supportive. Therapy with VASERETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Enalapril Maleate – Single oral doses of enalapril above 1,000 mg/kg and ≥ 1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure). Hydrochlorothiazide – Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. DOSAGE AND ADMINISTRATION Reference ID: 2916973 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 26 of 27 Enalapril and hydrochlorothiazide are effective treatments for hypertension. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single or two divided doses; hydrochlorothiazide is effective in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS) of enalapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of enalapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects but the addition of enalapril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose- independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy may be given VASERETIC 10-25. Further increases of enalapril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of hydrochlorothiazide. The daily dosage should not exceed two tablets of VASERETIC 10-25. Replacement Therapy: The combination may be substituted for the titrated components. Use in Renal Impairment: The usual regimens of therapy with VASERETIC need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73m2 (serum creatinine approximately ≤ 3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so enalapril maleate-hydrochlorothiazide is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure). HOW SUPPLIED Reference ID: 2916973 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLETS VASERETIC® (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) NDA 19-221 Proposed Labeling Page 27 of 27 VASERETIC Tablets 10-25 mg, are rust, oval shaped tablets, with one side “ VASE 10-25” and scored and the other side scored. Each tablet contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. They are supplied as follows: NDC 64455-146-01 bottles of 100 (with desiccant). Storage: Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided. Vaseretic® is a registered trademark of Biovail Laboratories International SRL. Manufactured in Canada by: Biovail Corporation Mississauga, ON Canada L5N 8M5 For: BTA Pharmaceuticals, Inc. (subsidiary of Biovail Corporation) Bridgewater, NJ 08807, USA Rev. 01/2011 LB0083-01 Reference ID: 2916973 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.063631	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019221s041lbl.pdf', 'application_number': 19221, 'submission_type': 'SUPPL ', 'submission_number': 41}
11,457	VASERETIC® TABLETS (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) Rx Only WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.  When pregnancy is detected, discontinue VASERETIC® as soon as possible.  Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity DESCRIPTION VASERETIC® (Enalapril Maleate-Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl) 3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is: Enalapril maleate is a white to off-white crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is: It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda VASERETIC is available in the tablet combination of enalapril maleate with hydrochlorothiazide: VASERETIC 10-25, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide. Inactive ingredients are: iron oxide, lactose, magnesium stearate, sodium bicarbonate, and starch. CLINICAL PHARMACOLOGY As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of enalapril maleate blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic. In clinical studies, the extent of blood pressure reduction seen with the combination of enalapril maleate and hydrochlorothiazide was approximately additive. The antihypertensive effect of VASERETIC was usually sustained for at least 24 hours. Concomitant administration of enalapril maleate and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities. Enalapril Maleate Mechanism of Action: Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril remains to be elucidated. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril maleate monotherapy than non-black patients. In contrast, hydrochlorothiazide was more effective in black patients than enalapril. Concomitant administration of enalapril maleate and hydrochlorothiazide was equally effective in black and non-black patients. Pharmacokinetics and Metabolism: Following oral administration of enalapril maleate, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalaprilat and enalapril is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at the rate of 62 mL/min. Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. Pharmacodynamics: Administration of enalapril maleate to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is infrequent with enalapril alone but it can be anticipated in volume-depleted patients, such as patients treated with diuretics. In clinical trials with enalapril and hydrochlorothiazide administered concurrently, syncope occurred in 1.3 percent of patients (see WARNINGS and DOSAGE AND ADMINISTRATION). In most patients studied, after oral administration of a single dose of enalapril maleate, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. At recommended doses, antihypertensive effects of enalapril maleate monotherapy have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval; this was less frequently observed with concomitant administration of enalapril maleate and hydrochlorothiazide. Achievement of optimal blood pressure reduction may require several weeks of enalapril therapy in some patients. The antihypertensive effects of enalapril have continued during long-term therapy. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In hemodynamic studies in patients with essential hypertension, blood pressure reduction produced by enalapril was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate (see PRECAUTIONS, Drug Interactions, Enalapril Maleate). Hydrochlorothiazide The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier. INDICATIONS AND USAGE VASERETIC is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial treatment (see DOSAGE AND ADMINISTRATION). In using VASERETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril does not have a similar risk (see WARNINGS). In considering use of VASERETIC, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema). CONTRAINDICATIONS VASERETIC is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not co-administer aliskiren with VASERETIC in patients with diabetes (see PRECAUTIONS, Drug Interactions). WARNINGS General Enalapril Maleate Hypotension: Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons such as those treated vigorously with diuretics or patients on dialysis. Syncope has been reported in 1.3 percent of patients receiving VASERETIC. In patients receiving enalapril alone, the incidence of syncope is 0.5 percent. The overall incidence of syncope may be reduced by proper titration of the individual components (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which usually can be given without difficulty once the blood pressure has increased after volume expansion. Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including VASERETIC) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases VASERETIC should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Neutropenia/Agranulocytosis: Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hydrochlorothiazide Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Enalapril Maleate and Hydrochlorothiazide). Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Embryo-fetal toxicity Pregnancy category D Enalapril Maleate Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Vaseretic as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Vaseretic, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Vaseretic for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use). No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the MRHDD. Enalapril-Hydrochlorothiazide There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of hydrochlorothiazide. These doses of enalapril are 4.3 and Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 26 times (mice and rats, respectively) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m2); the dose of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD. At these doses, fetotoxicity expressed as a decrease in average fetal weight occurred in both species. No fetotoxicity occurred at lower doses; 30/10 mg/kg/day of enalapril hydrochlorothiazide in rats and 10/10 mg/kg/day of enalapril-hydrochlorothiazide in mice. When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASERETIC should be discontinued as soon as possible (see Enalapril Maleate, Fetal Toxicity). Hydrochlorothiazide Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults. PRECAUTIONS General Enalapril Maleate Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldersterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death (see PRECAUTIONS, Drug Interactions). In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre existing renal impairment. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials treated with enalapril alone. In most cases these were isolated values which resolved despite continued therapy, although hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Hyperkalemia was less frequent (approximately 0.1 percent) in patients treated with enalapril plus hydrochlorothiazide. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hydrochlorothiazide Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Because enalapril reduces the production of aldosterone, concomitant therapy with enalapril attenuates the diuretic-induced potassium loss (see Drug Interactions, Agents Increasing Serum Potassium). Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life- threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy. The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Vaseretic during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with VASERETIC is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Enalapril Maleate Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on VASERETIC and other agents that affect the RAS. Do not co-administer aliskiren with VASERETIC in patients with diabetes. Avoid use of aliskiren with VASERETIC in patients with renal impairment (GFR <60 mL/min). Hypotension – Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. Other Cardiovascular Agents: Enalapril has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions. Agents Increasing Serium Potassium: Enalapril attenuates diuretic-induced potassium loss. Potassium- sparing diuretics (e.g., spironolactone, triameterene, or amiloride), potassium supplements, or potassium- containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VASERETIC. Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics – potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) – dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs – additive effect or potentiation. Cholestyramine and colestipol resins – Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) – possible increased responsiveness to the muscle relaxant. Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with VASERETIC. Non-steroidal Anti-inflammatory Drugs – In some patients, the administration of a non-steroidal anti- inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium- sparing and thiazide diuretics. Therefore, when VASERETIC and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Enalapril in combination with hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril-hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution assay in rat hepatocytes or chromosomal aberrations in an in vivo mouse bone marrow assay. Enalapril Maleate There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Hydrochlorothiazide Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in male and female rats at doses up to approximately 100 mg/kg/day (18 times the MRHDD when compared on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively, the MRHDD when compared on a body surface area basis. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Nursing Mothers Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Because of the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother. Pediatric Use Neonates with a history of in utero exposure to Vaseretic: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of VASERETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS VASERETIC has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with VASERETIC no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide. The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with VASERETIC in controlled clinical trials are shown below. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Percent of Patients in Controlled Studies VASERETIC (n=1580) Incidence (discontinuation) Placebo (n=230) Incidence Dizziness 8.6 (0.7) 4.3 Headache 5.5 (0.4) 9.1 Fatigue 3.9 (0.8) 2.6 Cough 3.5 (0.4) 0.9 Muscle Cramps 2.7 (0.2) 0.9 Nausea 2.5 (0.4) 1.7 Asthenia 2.4 (0.3) 0.9 Orthostatic Effects 2.3 (<0.1) 0.0 Impotence 2.2 (0.5) 0.5 Diarrhea 2.1 (<0.1) 1.7 Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain; Cardiovascular: Orthostatic hypotension, palpitation, tachycardia; Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth; Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo; Skin: Pruritus, rash; Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection. Angioedema: Angioedema has been reported in patients receiving VASERETIC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with VASERETIC should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients (see WARNINGS). Cough: See PRECAUTIONS, Cough. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6 percent of patients with essential hypertension treated with VASERETIC. More marked increases have been reported in other enalapril experience. Increases are more likely to occur in patients with renal artery stenosis (see PRECAUTIONS). Serum Uric Acid, Glucose, Magnesium, and Calcium: See PRECAUTIONS. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with VASERETIC but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity. Enalapril Maleate – Enalapril has been evaluated for safety in more than 10,000 patients. In clinical trials adverse reactions which occurred with enalapril were also seen with VASERETIC. However, since enalapril has been marketed, the following adverse reactions have been reported: Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid reactions during membrane exposure); Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; hypotension; angina pectoris, Raynaud's phenomenon; Digestive: lleus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis, dry mouth; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Nervous System/Psychiatric: Depression, confusion, ataxia, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality; Urogenital: Renal failure, oliguria, renal dysfunction, (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia; Respiratory: Pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection; Skin: Exfoliative dermatitits, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, tearing. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Hydrochlorothiazide – Body as a Whole: Weakness; Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia; Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: Transient blurred vision, xanthopsia. Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda OVERDOSAGE No specific information is available on the treatment of overdosage with VASERETIC. Treatment is symptomatic and supportive. Therapy with VASERETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Enalapril Maleate – Single oral doses of enalapril above 1,000 mg/kg and ≥ 1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure). Hydrochlorothiazide – Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. DOSAGE AND ADMINISTRATION Enalapril and hydrochlorothiazide are effective treatments for hypertension. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single or two divided doses; hydrochlorothiazide is effective in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS) of enalapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of enalapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects but the addition of enalapril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy may be given VASERETIC 10-25. Further increases of enalapril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of hydrochlorothiazide. The daily dosage should not exceed two tablets of VASERETIC 10-25. Replacement Therapy: The combination may be substituted for the titrated components. Use in Renal Impairment: The usual regimens of therapy with VASERETIC need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73m2 (serum creatinine approximately ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so enalapril maleate-hydrochlorothiazide is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure). Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda HOW SUPPLIED VASERETIC Tablets 10-25 mg are rust, oval-shaped tablets with one side imprinted with "VASE 10-25" and both sides scored. Each tablet contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. They are supplied as follows: NDC 0187-0146-01 bottles of 100 (with desiccant). Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided. Vaseretic® is a registered trademark of Valeant International Bermuda. Manufactured in Canada by: Valeant Pharmaceuticals International, Inc. Steinbach, MB Canada R5G 1Z7 For: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA Rev. 12/2014 9390801 Reference ID: 3678278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.307302	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019221s044lbl.pdf', 'application_number': 19221, 'submission_type': 'SUPPL ', 'submission_number': 44}
11,458	structural formula VASERETIC® TABLETS (ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE) Rx only WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue VASERETIC® as soon as possible. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity DESCRIPTION VASERETIC® (Enalapril Maleate-Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide. Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl) 3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is: Enalapril maleate is a white to off-white crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is: structural formula It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. VASERETIC is available in the tablet combination of enalapril maleate with hydrochlorothiazide: VASERETIC 10-25, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide. Inactive ingredients are: iron oxide, lactose, magnesium stearate, sodium bicarbonate, and starch. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of enalapril maleate blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic. In clinical studies, the extent of blood pressure reduction seen with the combination of enalapril maleate and hydrochlorothiazide was approximately additive. The antihypertensive effect of VASERETIC was usually sustained for at least 24 hours. Concomitant administration of enalapril maleate and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities. Enalapril Maleate Mechanism of Action: Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril remains to be elucidated. While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril maleate monotherapy than non-black patients. In contrast, hydrochlorothiazide was more effective in black patients than enalapril. Concomitant administration of enalapril maleate and hydrochlorothiazide was equally effective in black and non-black patients. Pharmacokinetics and Metabolism: Following oral administration of enalapril maleate, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalaprilat and enalapril is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at the rate of 62 mL/min. Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. Pharmacodynamics: Administration of enalapril maleate to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is infrequent with enalapril alone but it can be anticipated in volume-depleted patients, such as patients treated with diuretics. In clinical trials with enalapril and hydrochlorothiazide administered concurrently, syncope occurred in 1.3 percent of patients (see WARNINGS and DOSAGE AND ADMINISTRATION). In most patients studied, after oral administration of a single dose of enalapril maleate, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. At recommended doses, antihypertensive effects of enalapril maleate monotherapy have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval; this was less frequently observed with concomitant administration of enalapril maleate and hydrochlorothiazide. Achievement of optimal blood pressure reduction may require several weeks of enalapril therapy in some patients. The antihypertensive effects of enalapril have continued during long-term therapy. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In hemodynamic studies in patients with essential hypertension, blood pressure reduction produced by enalapril was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate, there is an Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate (see PRECAUTIONS, Drug Interactions, Enalapril Maleate). Hydrochlorothiazide The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier. INDICATIONS AND USAGE VASERETIC is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial treatment (see DOSAGE AND ADMINISTRATION). In using VASERETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril does not have a similar risk (see WARNINGS). In considering use of VASERETIC, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema). CONTRAINDICATIONS VASERETIC is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer aliskiren with VASERETIC in patients with diabetes (see PRECAUTIONS, DrugInteractions). Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS General Enalapril Maleate Hypotension: Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons such as those treated vigorously with diuretics or patients on dialysis. Syncope has been reported in 1.3 percent of patients receiving VASERETIC. In patients receiving enalapril alone, the incidence of syncope is 0.5 percent. The overall incidence of syncope may be reduced by proper titration of the individual components (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which usually can be given without difficulty once the blood pressure has increased after volume expansion. Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including VASERETIC) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. This may occur at any time during treatment. In such cases VASERETIC should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see PRECAUTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Neutropenia/Agranulocytosis: Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Hydrochlorothiazide Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Enalapril Maleate and Hydrochlorothiazide). Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Fetal Toxicity Pregnancy Category D Enalapril Maleate Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue VASERETIC as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue VASERETIC, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to VASERETIC for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use). No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the MRHDD. Enalapril-Hydrochlorothiazide Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of hydrochlorothiazide. These doses of enalapril are 4.3 and 26 times (mice and rats, respectively) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m2); the dose of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD. At these doses, fetotoxicity expressed as a decrease in average fetal weight occurred in both species. No fetotoxicity occurred at lower doses; 30/10 mg/kg/day of enalapril hydrochlorothiazide in rats and 10/10 mg/kg/day of enalapril-hydrochlorothiazide in mice. When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASERETIC should be discontinued as soon as possible (see Enalapril Maleate, Fetal Toxicity). Hydrochlorothiazide Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults. PRECAUTIONS General Enalapril Maleate Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldersterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death (see PRECAUTIONS, Drug Interactions). In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre existing renal impairment. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Evaluation of the hypertensive patient should always include assessment of renal function. Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials treated with enalapril alone. In most cases these were isolated values which resolved despite continued therapy, although hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Hyperkalemia was less frequent (approximately 0.1 percent) in patients treated with enalapril plus hydrochlorothiazide. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hydrochlorothiazide Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Because enalapril reduces the production of aldosterone, concomitant therapy with enalapril attenuates the diuretic-induced potassium loss (see Drug Interactions, Agents Increasing Serum Potassium). Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life- threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy. The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to VASERETIC during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with VASERETIC is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Enalapril Maleate Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on VASERETIC and other agents that affect the RAS. Do not coadminister aliskiren with VASERETIC in patients with diabetes. Avoid use of aliskiren with VASERETIC in patients with renal impairment (GFR <60 mL/min). Hypotension – Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-steroidal Anti-inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. Other Cardiovascular Agents: Enalapril has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions. Agents Increasing Serum Potassium: Enalapril attenuates diuretic-induced potassium loss. Potassium- sparing diuretics (e.g., spironolactone, triameterene, or amiloride), potassium supplements, or potassium- containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VASERETIC. mTOR (mammalian target of rapamycin) inhibitors Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS) Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics – potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) – dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs – additive effect or potentiation. Cholestyramine and colestipol resins – Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) – possible increased responsiveness to the muscle relaxant. Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with VASERETIC. Non-steroidal Anti-inflammatory Drugs – In some patients, the administration of a non-steroidal anti- inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium- sparing and thiazide diuretics. Therefore, when VASERETIC and non-steroidal anti-inflammatory agents Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Carcinogenesis, Mutagenesis, Impairment of Fertility Enalapril in combination with hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril-hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution assay in rat hepatocytes or chromosomal aberrations in an in vivo mouse bone marrow assay. Enalapril Maleate There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Hydrochlorothiazide Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in male and female rats at doses up to approximately 100 mg/kg/day (18 times the MRHDD when compared on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively, the MRHDD when compared on a body surface area basis. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy Nursing Mothers Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Because of the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother. Pediatric Use Neonates with a history of in utero exposure to VASERETIC: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of VASERETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS VASERETIC has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with VASERETIC no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide. The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with VASERETIC in controlled clinical trials are shown below. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Percent of Patients in Controlled Studies VASERETIC (n=1580) Incidence (discontinuation) Placebo (n=230) Incidence Dizziness 8.6 (0.7) 4.3 Headache 5.5 (0.4) 9.1 Fatigue 3.9 (0.8) 2.6 Cough 3.5 (0.4) 0.9 Muscle Cramps 2.7 (0.2) 0.9 Nausea 2.5 (0.4) 1.7 Asthenia 2.4 (0.3) 0.9 Orthostatic Effects 2.3 (<0.1) 0.0 Impotence 2.2 (0.5) 0.5 Diarrhea 2.1 (<0.1) 1.7 Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain; Cardiovascular: Orthostatic hypotension, palpitation, tachycardia; Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth; Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo; Skin: Pruritus, rash; Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection. Angioedema: Angioedema has been reported in patients receiving VASERETIC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with VASERETIC should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients (see WARNINGS). Cough: See PRECAUTIONS, Cough. Clinical Laboratory Test Findings Serum Electrolytes: See PRECAUTIONS. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6 percent of patients with essential hypertension treated with VASERETIC. More marked increases have been reported in other enalapril experience. Increases are more likely to occur in patients with renal artery stenosis (see PRECAUTIONS). Serum Uric Acid, Glucose, Magnesium, and Calcium: See PRECAUTIONS. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with VASERETIC but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity. Enalapril Maleate – Enalapril has been evaluated for safety in more than 10,000 patients. In clinical trials adverse reactions which occurred with enalapril were also seen with VASERETIC. However, since enalapril has been marketed, the following adverse reactions have been reported: Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid reactions during membrane exposure); Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; hypotension; angina pectoris, Raynaud's phenomenon; Digestive: lleus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis, dry mouth; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Nervous System/Psychiatric: Depression, confusion, ataxia, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality; Urogenital: Renal failure, oliguria, renal dysfunction, (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia; Respiratory: Pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, pneumonia, bronchitis, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection; Skin: Exfoliative dermatitits, toxic epidermal necrolysis, Stevens-Johnson syndrome, herpes zoster, erythema multiforme, urticaria, pemphigus, alopecia, flushing, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, conjunctivitis, dry eyes, tearing. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Hydrochlorothiazide – Body as a Whole: Weakness; Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia; Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions; Musculoskeletal: Muscle spasm; Nervous System/Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: Transient blurred vision, xanthopsia. Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. OVERDOSAGE No specific information is available on the treatment of overdosage with VASERETIC. Treatment is symptomatic and supportive. Therapy with VASERETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures. Enalapril Maleate – Single oral doses of enalapril above 1,000 mg/kg and ≥ 1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure). Hydrochlorothiazide – Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. DOSAGE AND ADMINISTRATION Enalapril and hydrochlorothiazide are effective treatments for hypertension. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single or two divided doses; hydrochlorothiazide is effective in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS) of enalapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of enalapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects but the addition of enalapril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy may be given VASERETIC 10-25. Further increases of enalapril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of hydrochlorothiazide. The daily dosage should not exceed two tablets of VASERETIC 10-25. Replacement Therapy: The combination may be substituted for the titrated components. Use in Renal Impairment: The usual regimens of therapy with VASERETIC need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine approximately ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda enalapril maleate-hydrochlorothiazide is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure). HOW SUPPLIED VASERETIC Tablets 10-25 mg are rust, oval-shaped tablets with one side imprinted with "VASE 10-25" and both sides scored. Each tablet contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. They are supplied as follows: NDC 0187-0146-01 bottles of 100 (with desiccant). Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from moisture. Dispense in a tight container as per USP, if product package is subdivided. Vaseretic® is a registered trademark of Valeant Pharmaceuticals North America LLC. Manufactured in Canada by: Valeant Pharmaceuticals International, Inc. Steinbach, MB Canada R5G 1Z7 For: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA Rev. 08/15 New Valeant p/n Reference ID: 3811047 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.388090	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019221s045lbl.pdf', 'application_number': 19221, 'submission_type': 'SUPPL ', 'submission_number': 45}
11,454	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. -------------------------------------------------------------------------------------------------------- /s/ --------------------- Wiley Chambers 8/8/01 10:56:30 AM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.526015	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19219s20lbl.pdf', 'application_number': 19219, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,459	1 CARNITOR® (levocarnitine) Tablets (330 mg) CARNITOR® (levocarnitine) Oral Solution (1 g per 10 mL multidose) CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution (1 g per 10 mL multidose) For oral use only. Not for parenteral use. DESCRIPTION CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane. The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1- propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is: C H O H CH2 CH2COO (CH3)3N - + Empirical Formula: C7H15NO3 Molecular Weight: 161.20 Each CARNITOR® (levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone. Each 118 mL container of CARNITOR® (levocarnitine) Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. Each 118 mL container of CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Natural Cherry Flavor, D,L,-Malic Acid, Purified Water, Sodium Saccharin USP. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. CLINICAL PHARMACOLOGY CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with CARNITOR®. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life- threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations. PHARMACOKINETICS In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours. The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR®, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution. Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h. Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9 METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion). INDICATIONS AND USAGE CARNITOR® (levocarnitine) is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient. CARNITOR® (levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency. CONTRAINDICATIONS None known. WARNINGS None. PRECAUTIONS General CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution are for oral/internal use only. Not for parenteral use. Gastrointestinal reactions may result from a too rapid consumption of carnitine. CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. They should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance. The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. Carcinogenesis, mutagenesis, impairment of fertility Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Pregnancy Pregnancy Category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to CARNITOR®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Levocarnitine supplementation in nursing mothers has not been specifically studied. Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment. Pediatric Use See Dosage and Administration. ADVERSE REACTIONS Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases. Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported. OVERDOSAGE There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea. DOSAGE AND ADMINISTRATION CARNITOR® (levocarnitine) Tablets. Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg tablets, depending on clinical response. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Infants and children: The recommended oral dosage for infants and children is between 50 and 100 mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact dosage will depend on clinical response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition. CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. For oral use only. Not for parenteral use. Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition. Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition. CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance. HOW SUPPLIED CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in individual blisters, packaged in boxes of 90 (NDC 54482-144-07). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Tablets are manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy. CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701. CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 54482-148-01). Store at controlled room temperature (25°C). See USP. CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701. CARNITOR® (levocarnitine) is also available in the following dosage forms for intravenous injection: CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy or Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591. Rx only. REFERENCES 1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61. 2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568. 3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577. 4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702. 5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540. 6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66. 7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill. 8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press. 9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368. 10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310. Date of Issue: 06/06 OPI-7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.546099	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018948s024,019257s011lbl.pdf', 'application_number': 19257, 'submission_type': 'SUPPL ', 'submission_number': 11}
11,463	NDA 19-261/S-008 Page 3 PAREMYD (hydroxyamphetamine hydrobromide/ tropicamide ophthalmic solution) 1%/0.25% sterile DESCRIPTION PAREMYD sterile ophthalmic solution is a topical mydriatic combination product for ophthalmic use. STRUCTURAL FORMULAE: [STRUCTURE] [STRUCTURE] hydroxyamphetamine hydrobromide tropicamide CHEMICAL NAME: Hydroxyamphetamine hydrobromide: Phenol, 4-(2-aminopropyl)-, hydrobromide Tropicamide: Benzeneacetamide, N-ethyl--(hydroxymethyl)-N-(4-pyridinylmethyl)- CONTAINS: Actives: Hydroxyamphetamine hydrobromide, USP 1.0% Tropicamide, USP 0.25% Preservative: benzalkonium chloride 0.005%; Inactives: edetate disodium 0.015%; sodium chloride; and purified water. Hydrochloric acid and/or sodium hydroxide are added to adjust the pH. The pH of PAREMYD can range from 4.2 to 5.8 during its shelf life. The osmolality of PAREMYD is approximately 307 mOsm/l. CLINICAL PHARMACOLOGY PAREMYD Solution combines the effects of the adrenergic agent, hydroxyamphetamine hydrobromide, and the anticholinergic agent, tropicamide. Hydroxyamphetamine hydrobromide is an indirectly-acting sympathomimetic agent which, when applied topically to the eye, causes the release of endogenous norepinephrine from intact adrenergic nerve terminals resulting in mydriasis. Since hydroxyamphetamine hydrobromide has little or no direct activity on the receptor site, dilation does not usually occur if there is damage to the presynaptic nerve terminal, e.g., Horner’s Syndrome. However, it is not known whether damage to the presynaptic nerve terminal will influence the extent of mydriasis produced by PAREMYD. Hydroxyamphetamine hydrobromide has minimal cycloplegic action. Tropicamide is a parasympatholytic agent which, when applied topically to the eye, blocks the responses of the sphincter muscle of the iris and the ciliary muscle to cholinergic stimulation, producing dilation of the pupil and paralysis of the ciliary muscle. Tropicamide produces short-duration mydriasis. Although cycloplegia occurs with higher doses of tropicamide, there is evidence with 0.25% tropicamide that full cycloplegia does not occur. Since both these agents act on different effector sites, their simultaneous use produces an additive This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-261/S-008 Page 4 mydriatic effect. PAREMYD provides diminished pupil responsiveness to light, facilitating ophthalmoscopy. The onset of action with PAREMYD occurs within 15 minutes, followed by maximum effect within 60 minutes after instillation of one drop. Clinically significant dilation, inhibition of pupillary light response, and partial cycloplegia last 3 hours, with recovery beginning at approximately 90 minutes and with complete recovery occurring in most patients in 6 to 8 hours. However, in some cases complete recovery may take up to 24 hours. Effectiveness may differ slightly in patients with light and dark irides, with those patients with light irides experiencing a slightly greater mydriasis. INDICATIONS PAREMYD Solution is indicated for mydriasis in routine diagnostic procedures and in conditions where short-term pupil dilation is desired. PAREMYD provides clinically significant mydriasis with partial cycloplegia. CONTRAINDICATIONS PAREMYD Solution should not be used in patients with angle-closure glaucoma or in those with narrow angles in whom dilation of the pupil may precipitate an attack of angle-closure glaucoma. This product is also contraindicated in patients who are hypersensitive to any of its components. WARNINGS For topical ophthalmic use only; not for injection. There is evidence that mydriatics may produce a transient elevation of intraocular pressure in patients with open angle glaucoma. This preparation rarely may cause CNS disturbances which may be particularly dangerous in infants, children or the aged. Psychotic reactions, behavioral disturbances and vasomotor or cardio-respiratory collapse have been reported with the use of anticholinergic drugs. PRECAUTIONS General: Patients with hypertension, hyperthyroidism, diabetes or cardiac disease (i.e., arrhythmias or chronic ischemic heart disease) should be monitored after instillation. The elderly and others in whom glaucoma or increased intraocular pressure may be encountered following administration of PAREMYD Solution should also be monitored closely. To avoid inducing angle-closure glaucoma, an estimation of the depth of the angle of the anterior chamber should be made. Information for Patients: Patients should be advised not to touch the dropper tip to any surface since this may contaminate the solution. Patients should be advised to use caution when driving or engaging in other hazardous activities while pupils are dilated. Patients may experience photophobia and/or blurred vision and should protect their eyes in bright illumination when pupils are dilated. Parents should be warned not to get this preparation in their child's mouth and to wash their own hands and the child's hands following administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-261/S-008 Page 5 Carcinogenesis, mutagenesis, impairment of fertility: No studies have been performed to evaluate the carcinogenic, mutagenic or impairment of fertility potential of PAREMYD. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with PAREMYD. It is also not known whether PAREMYD can cause fetal harm when administered to a pregnant woman or can affect reproduction capability. PAREMYD should be given to a pregnant woman only if clearly needed. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PAREMYD is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. PAREMYD may rarely cause CNS disturbances which may be dangerous in infants and children. Psychotic reactions, behavioral disturbances and vasomotor or cardio-respiratory collapse in children have been reported with the use of anticholinergic drugs. (See Warnings). Keep this and all medications out of the reach of children. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients ADVERSE REACTIONS Increased intraocular pressure has been reported following use of mydriatics. Transient stinging, dryness of the mouth, blurred vision, photophobia with or without corneal staining, tachycardia, headache, allergic reactions, nausea, vomiting, pallor and muscle rigidity have been reported with the use of tropicamide and/or hydroxyamphetamine hydrobromide, and thus may occur with PAREMYD Solution. Central nervous system disturbances have also been reported. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse have been reported with the use of anticholinergic drugs. Rare but serious cardiovascular events, including death due to myocardial infarction, ventricular fibrillation and significant hypotensive episodes have occurred shortly following PAREMYD instillation. OVERDOSAGE Ocular overdosage will cause dilation of the pupils. Systemic overdosage or ingestion of large doses may result in hypertension, cardiac arrhythmias, sub-sternal discomfort, headache, sweating, nausea, vomiting and gastrointestinal irritation. Patients with systemic overdosage should be carefully monitored and treated symptomatically. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-261/S-008 Page 6 DOSAGE AND ADMINISTRATION One to two drops in the conjunctival sac. The onset of action with PAREMYD Solution occurs within 15 minutes followed by maximum effect within 60 minutes. Clinically significant dilation, inhibition of pupillary light response, and partial cycloplegia last 3 hours. Mydriasis will reverse spontaneously with time, typically in 6 to 8 hours. However, in some cases, complete recovery may take up to 24 hours. HOW SUPPLIED PAREMYD (hydroxyamphetamine hydrobromide/ tropicamide ophthalmic solution) 1%/0.25% as a 15 mL solution in a 15 mL opaque white, low density polyethylene bottle with a natural low density polyethylene dropper tip and a red polypropylene cap. 15 mL- NDC 17478-704-12 Note: Protect from light. Store between 15ºC to 25ºC (59ºF to 77ºF). Rx only. MANUFACTURED BY: AKORN, INC. SOMERSET, NJ 08873 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Wiley Chambers 12/4/01 01:47:27 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.796910	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19261s8lbl.pdf', 'application_number': 19261, 'submission_type': 'SUPPL ', 'submission_number': 8}
11,461	PSORCON® E Emollient Cream (diflorasone diacetate cream) 0.05% Prescribing Information as of December 2001. Not For Ophthalmic Use DESCRIPTION Each gram of Psorcon E Emollient Cream contains 0.5 mg diflorasone diacetate in a cream base. Chemically, diflorasone diacetate is: 6α,9-difluoro - 11ß,17,21 - trihydroxy - 16ß - methyl-pregna - 1,4 - diene - 3,20 - dione 17,21- diacetate. The structural formula is represented below: Each gram of Psorcon E Emollient Cream contains 0.5 mg diflorasone diacetate in a hydrophilic vanishing cream base of propylene glycol, stearyl alcohol, cetyl alcohol, sorbitan monostearate, polysorbate 60, mineral oil and purified water. CLINICAL PHARMACOLOGY Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlu- sive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.) Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. They are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. O CH3 F F H H HO H H CH3 CH3 H OCCH3 O C O CH2OCCH3 O 50065635 0817504005 Prescribing Information as of December 2001. Emollient Cream diflorasonediacetate cream 0.05% ® ™ This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Topical corticosteroids are indicated for relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. CONTRAINDICATIONS Topical steroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. PRECAUTIONS General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic- pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppres- sion by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS: Pediatric Use.) If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlu- sive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on an infant or child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests: The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy Category C: Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically admin- istered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness of Psorcon E (diflorasone diacetate cream) in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing’s syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ADVERSE REACTIONS The following local adverse reactions have been reported with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approx- imate decreasing order of occurrence: 1. Burning 9. Perioral dermatitis 2. Itching 10. Allergic contact dermatitis 3. Irritation 11. Maceration of the skin 4. Dryness 12. Secondary infection 5. Folliculitis 13. Skin atrophy 6. Hypertrichosis 14. Striae 7. Acneiform eruptions 15. Miliaria 8. Hypopigmentation OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS.) DOSAGE AND ADMINISTRATION Psorcon E Emollient Cream should be applied to the affected areas as a thin film from one to three times daily depending on the severity or resistant nature of the condition. Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions. If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy initiated. HOW SUPPLIED Psorcon E Emollient Cream is available in the following size tubes: 15 gram NDC 0066–0272–17 30 gram NDC 0066–0272–31 60 gram NDC 0066–0272–60 Store at controlled room temperature, 20° to 25° C (68° to 77° F) [see USP]. Prescribing Information as of December 2001. Rx only Manufactured for Dermik Laboratories, Inc. Berwyn, PA USA 19312 By Pharmacia & Upjohn Company A subsidiary of Pharmacia Corporation Kalamazoo, MI, USA 49001 Revised December 2001 817 504 005 50065635 691694 PSORCON® E Emollient Cream (diflorasone diacetate cream) 0.05% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.807112	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19259slr009_psorcon_lbl.pdf', 'application_number': 19259, 'submission_type': 'SUPPL ', 'submission_number': 9}
11,460	s t r u c t u ral f or m ula CARNITOR® (levocarnitine) Tablets (330 mg) CARNITOR® (levocarnitine) Oral Solution (1 g per 10 mL multidose) CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution (1 g per 10 mL multidose) For oral use only. Not for parenteral use. DESCRIPTION CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane. The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1 propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is: Each CARNITOR® (levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone. Each 118 mL container of CARNITOR® (levocarnitine) Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. Each 118 mL container of CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Natural Cherry Flavor, D,L,-Malic Acid, Purified Water, Sodium Saccharin USP. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. CLINICAL PHARMACOLOGY CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with CARNITOR® . The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6 Reference ID: 3767718 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life- threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations. PHARMACOKINETICS In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours. The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR® , calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution. Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h. Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9 METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10 Reference ID: 3767718 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion). INDICATIONS AND USAGE CARNITOR® (levocarnitine) is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient. CARNITOR® (levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency. CONTRAINDICATIONS None known. WARNINGS None. PRECAUTIONS General CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution are for oral/internal use only. Not for parenteral use. Gastrointestinal reactions may result from a too rapid consumption of carnitine. CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. They should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance. The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. Drug Interactions Reports of INR increase with the use of warfarin have been observed. It is recommended that INR levels be monitored in patients on warfarin therapy after the initiation of treatment with levocarnitine or after dose adjustments. Reference ID: 3767718 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine. Pregnancy Pregnancy Category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to CARNITOR® . There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Levocarnitine supplementation in nursing mothers has not been specifically studied. Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment. Pediatric Use See Dosage and Administration. ADVERSE REACTIONS Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases. Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported. OVERDOSAGE There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea. DOSAGE AND ADMINISTRATION CARNITOR® (levocarnitine) Tablets. Reference ID: 3767718 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg tablets, depending on clinical response. Infants and children: The recommended oral dosage for infants and children is between 50 and 100 mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact dosage will depend on clinical response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition. CARNITOR® (levocarnitine) Oral Solution and CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. For oral use only. Not for parenteral use. Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition. Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition. CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance. HOW SUPPLIED CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in individual blisters, packaged in boxes of 90 (NDC 54482-144-07). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Tablets are manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy. CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701. Reference ID: 3767718 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-148-01). Store at controlled room temperature (25°C). See USP. CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701. Rx only. REFERENCES 1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61. 2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568. 3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577. 4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702. 5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540. 6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66. 7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill. 8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press. 9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368. 10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310. company logo PREVIOUS EDITION IS OBSOLETE Date of Issue: 04/15 OPI-8 Reference ID: 3767718 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CARNITOR® (levocarnitine) Injection 1 g per 5 mL vial FOR INTRAVENOUS USE ONLY. DESCRIPTION CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane. The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1 propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is: HO H C (CH3)3N+ CH2 CH2COO - Empirical Formula: C7H15NO3 Molecular Weight: 161.20 CARNITOR® (levocarnitine) Injection is a sterile aqueous solution containing 1 g of levocarnitine per 5 mL vial. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid or sodium hydroxide. CLINICAL PHARMACOLOGY CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with CARNITOR® . The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6 Secondary carnitine deficiency can be a consequence of inborn errors of metabolism or iatrogenic factors such as hemodialysis. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of Reference ID: 3767718 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations. End Stage Renal Disease (ESRD) patients on maintenance hemodialysis may have low plasma carnitine concentrations and an increased ratio of acylcarnitine/carnitine because of reduced intake of meat and dairy products, reduced renal synthesis and dialytic losses. Certain clinical conditions common in hemodialysis patients such as malaise, muscle weakness, cardiomyopathy and cardiac arrhythmias may be related to abnormal carnitine metabolism. Pharmacokinetic and clinical studies with CARNITOR® have shown that administration of levocarnitine to ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations. PHARMACOKINETICS In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours. The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR® , calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution. Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h. Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9 In a 9-week study, 12 ESRD patients undergoing hemodialysis for at least 6 months received CARNITOR® 20 mg/kg three times per week after dialysis. Prior to initiation of CARNITOR® therapy, mean plasma levocarnitine concentrations were approximately 20 µmol/L pre-dialysis and 6 µmol/L post-dialysis. The table summarizes the pharmacokinetic data (mean ± SD µmol/L) after the first dose of CARNITOR® and after 8 weeks of CARNITOR® therapy. N=12 Baseline Single dose 8 weeks Cmax - 1139 ± 240 1190 ± 270 Trough (pre-dialysis, pre-dose) 21.3 ± 7.7 68.4 ± 26.1 190 ± 55 Reference ID: 3767718 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After one week of CARNITOR® therapy (3 doses), all patients had trough concentrations between 54 and 180 µmol/L (normal 40-50 µmol/L) and concentrations remained relatively stable or increased over the course of the study. In a similar study in ESRD patients also receiving 20 mg/kg CARNITOR® 3 times per week after hemodialysis, 12- and 24-week mean pre-dialysis (trough) levocarnitine concentrations were 189 (N=25) and 243 (N=23) µmol/L, respectively. In a dose-ranging study in ESRD patients undergoing hemodialysis, patients received 10, 20, or 40 mg/kg CARNITOR® 3 times per week following dialysis (N~30 for each dose group). Mean ± SD trough levocarnitine concentrations (µmol/L) by dose after 12 and 24 weeks of therapy are summarized in the table. 12 weeks 24 weeks 10 mg/kg 116 ± 69 148 ± 50 20 mg/kg 210 ± 58 240 ± 60 40 mg/kg 371 ± 111 456 ± 162 While the efficacy of CARNITOR® to increase carnitine concentrations in patients with ESRD undergoing dialysis has been demonstrated, the effects of supplemental carnitine on the signs and symptoms of carnitine deficiency and on clinical outcomes in this population have not been determined. METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10 After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion). INDICATIONS AND USAGE For the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency. For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. CONTRAINDICATIONS None known. WARNINGS None. Reference ID: 3767718 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PRECAUTIONS General The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. Drug Interactions Reports of INR increase with the use of warfarin have been observed. It is recommended that INR levels be monitored in patients on warfarin therapy after the initiation of treatment with levocarnitine or after dose adjustments. Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine. Pregnancy Pregnancy Category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to CARNITOR®. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Levocarnitine supplementation in nursing mothers has not been specifically studied. Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment. Pediatric Use See Dosage and Administration. ADVERSE REACTIONS Transient nausea and vomiting have been observed. Less frequent adverse reactions are body odor, nausea, and gastritis. An incidence for these reactions is difficult to estimate due to the confounding effects of the underlying pathology. Seizures have been reported to occur in patients, with or without pre-existing seizure activity, receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported. Reference ID: 3767718 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The table below lists the adverse events that have been reported in two double-blind, placebo- controlled trials in patients on chronic hemodialysis. Events occurring at ≥5% are reported without regard to causality. Adverse Events with a Frequency ≥5% Regardless of Causality by Body System Placebo (n=63) Levocarnitine 10 mg (n=34) Levocarnitine 20 mg (n=62) Levocarnitine 40 mg (n=34) Levocarnitine 10, 20 & 40 mg (n=130) Body as Whole Abdominal pain 17 21 5 6 9 Accidental injury 10 12 8 12 10 Allergic reaction 5 6 2 Asthenia 8 9 8 12 9 Back pain 10 9 8 6 8 Chest pain 14 6 15 12 12 Fever 5 6 5 12 7 Flu syndrome 40 15 27 29 25 Headache 16 12 37 3 22 Infection 17 15 10 24 15 Injection site reaction 59 38 27 38 33 Pain 49 21 32 35 30 Cardiovascular Arrhythmia 5 3 3 2 Atrial fibrillation 2 6 2 Cardiovascular disorder 6 3 5 6 5 Electrocardiogram abnormal 3 6 2 Hemorrhage 6 9 2 3 4 Hypertension 14 18 21 21 20 Hypotension 19 15 19 3 14 Palpitations 3 8 5 Tachycardia 5 6 5 9 6 Vascular disorder 2 2 6 2 Digestive Anorexia 3 3 5 6 5 Constipation 6 3 3 3 3 Diarrhea 19 9 10 35 16 Dyspepsia 10 9 6 5 Gastrointestinal disorder 2 3 6 2 Melena 3 6 2 Nausea 10 9 5 12 8 Stomach atony 5 Vomiting 16 9 16 21 15 Endocrine System Parathyroid disorder 2 6 2 6 4 Hemic/Lymphatic Anemia 3 3 5 12 6 Metabolic/Nutritional Hypercalcemia 3 15 8 6 9 Hyperkalemia 6 6 6 6 6 Hypervolemia 17 3 3 12 5 Reference ID: 3767718 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Peripheral edema 3 6 5 3 5 Weight decrease 3 3 8 3 5 Weight increase 2 3 6 2 Musculo-Skeletal Leg cramps 13 8 4 Myalgia 6 Nervous Anxiety 5 2 1 Depression 3 6 5 6 5 Dizziness 11 18 10 15 13 Drug dependence 2 6 2 Hypertonia 5 3 1 Insomnia 6 3 6 4 Paresthesia 3 3 3 12 5 Vertigo 6 2 Respiratory Bronchitis 5 3 3 Cough increase 16 10 18 9 Dyspnea 19 3 11 3 7 Pharyngitis 33 24 27 15 23 Respiratory disorder 5 Rhinitis 10 6 11 6 9 Sinusitis 5 2 3 2 Skin And Appendages Pruritus 13 8 3 5 Rash 3 5 3 3 Special Senses Amblyopia 2 6 3 Eye disorder 3 6 3 3 Taste perversion 2 9 3 Urogenital Urinary tract infect 6 3 3 2 Kidney failure 5 6 6 6 6 OVERDOSAGE There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea. DOSAGE AND ADMINISTRATION CARNITOR® Injection is administered intravenously. Metabolic Disorders The recommended dose is 50 mg/kg given as a slow 2-3 minute bolus injection or by infusion. Often a loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as therapy may require. The highest dose administered has been 300 mg/kg. Reference ID: 3767718 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be between 35 and 60 µmol/L) and overall clinical condition. ESRD Patients on Hemodialysis The recommended starting dose is 10-20 mg/kg dry body weight as a slow 2-3 minute bolus injection into the venous return line after each dialysis session. Initiation of therapy may be prompted by trough (pre-dialysis) plasma levocarnitine concentrations that are below normal (40-50 µmol/L). Dose adjustments should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments (e.g. to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COMPATIBILITY AND STABILITY CARNITOR® Injection is compatible and stable when mixed in parenteral solutions of Sodium Chloride 0.9% or Lactated Ringer's in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags. HOW SUPPLIED CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy. Store vials at controlled room temperature (25°C). See USP. Discard unused portion of an opened vial, as the formulation does not contain a preservative. US Patent Nos. 6,335,369; 6,429,230; 6,696,493 Rx only. REFERENCES 1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61. 2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568. 3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577. 4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702. 5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540. 6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66. 7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill. Reference ID: 3767718 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press. 9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368. 10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310. company logo PREVIOUS EDITION IS OBSOLETE Date of Issue: 04/15 VPI-12 Reference ID: 3767718 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.923812	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018948s026,019257s012,020182s013lbl.pdf', 'application_number': 19257, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,462	Prescribing Information as of December 2001. psorcon® ointment brand of diflorasone diacetate 0.05% Not For Ophthalmic Use DESCRIPTION Each gram of psorcon Ointment contains 0.5 mg diflorasone diacetate in an ointment base. Chemically, diflorasone diacetate is 6α, 9-difluoro-11ß,17,21-trihydroxy-16ß-methylpregna-1,4- diene-3,20-dione 17,21-diacetate. The structural formula is represented below: Each gram of psorcon Ointment contains 0.5 mg diflorasone diacetate in an ointment base of propylene glycol, glyceryl monostearate and white petrolatum. CLINICAL PHARMACOLOGY Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlu- sive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable thera- peutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.) Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. They are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. O CH3 F F H H HO H H CH3 CH3 H OCCH3 O C O CH2OCCH3 O 50065612 0813377212 Prescribing Information as of December 2001. psorcon® ointment diflorasone diacetate ointment 0.05% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Layout and/or size adjusted for ease of reading and printing. INDICATIONS AND USAGE Topical corticosteroids are indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. CONTRAINDICATIONS Topical steroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. PRECAUTIONS General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic- pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppres- sion by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS — Pediatric Use.) If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on an infant or child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests: The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy Category C: Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically admin- istered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness of psorcon (diflorasone diacetate ointment) in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insuffi- ciency after withdrawal of treatment and of Cushing’s syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ADVERSE REACTIONS The following local adverse reactions have been reported with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are listed in approxi- mate decreasing order of occurrence: 1. Burning 2. Itching 3. Irritation 4. Dryness 5. Folliculitis 6. Hypertrichosis 7. Acneiform eruptions 8. Hypopigmentation 9. Perioral dermatitis 10. Allergic contact dermatitis 11. Maceration of the skin 12. Secondary infection 13. Skin atrophy 14. Striae 15. Miliaria OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS.) DOSAGE AND ADMINISTRATION psorcon Ointment should be applied to the affected area as a thin film from one to three times daily depending on the severity or resistant nature of the condition. Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions. If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy initiated. HOW SUPPLIED psorcon Ointment 0.05% is available in the following size tubes: 60 gram NDC 0066-0071-60 Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Prescribing Information as of December 2001. Rx only Manufactured by Pharmacia & Upjohn Company A subsidiary of Pharmacia Corporation Kalamazoo, MI, USA 49001 For Dermik Laboratories, Inc. Berwyn, PA USA 19312 Revised December 2001 813 377 212 50065612 691694 psorcon® ointment brand of diflorasone diacetate 0.05% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:18.987635	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019260s007lbl.pdf', 'application_number': 19260, 'submission_type': 'SUPPL ', 'submission_number': 7}
11,466	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:19.137605	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/019279s010lbl.pdf', 'application_number': 19279, 'submission_type': 'SUPPL ', 'submission_number': 10}
11,465	Cytotec® misoprostol tablets WARNINGS CYTOTEC (MISOPROSTOL) ADMINISTRATION TO WOMEN WHO ARE PREGNANT CAN CAUSE BIRTH DEFECTS, ABORTION, OR PREMATURE BIRTH. UTERINE RUPTURE HAS BEEN REPORTED WHEN CYTOTEC WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS and LABOR AND DELIVERY). CYTOTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN TO REDUCE THE RISK OF ULCERS INDUCED BY NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Cytotec should not be used for reducing the risk of NSAID-induced ulcers in women of childbearing potential unless the patient is at high risk of complications from gastric ulcers associated with use of the NSAID, or is at high risk of developing gastric ulceration. In such patients, Cytotec may be prescribed if the patient • has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. • is capable of complying with effective contraceptive measures. • has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. • will begin Cytotec only on the second or third day of the next normal menstrual period. DESCRIPTION Cytotec oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E1 analog. Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±): 1 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda structural formula Misoprostol is a water-soluble, viscous liquid. Inactive ingredients of tablets are hydrogenated castor oil, hypromellose, microcrystalline cellulose, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacokinetics: Misoprostol is extensively absorbed, and undergoes rapid de esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs. In normal volunteers, Cytotec (misoprostol) is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20–40 minutes. There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show a linear relationship with dose over the range of 200–400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. 2 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ... Mean ± SD Cmax(pg/ml) AUC(0–4) (pg·hr/ml) Tmax(min) Fasting With Antacid 811 ± 317 689 ± 315 417 ± 135 349 ± 108* 14 ± 8 20 ± 14 With High Fat Breakfast 303 ± 176* 373 ± 111 64 ± 79* * Comparisons with fasting results statistically significant, p<0.05. After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T1/2, Cmax, and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant. Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. The serum protein binding of misoprostol acid is less than 90% and is concentration- independent in the therapeutic range. After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/ml (CV 37%) and 20.9 pg/ml (CV 62%) after single 200 µg and 600 µg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/ml at 5 hours post-dose. Pharmacodynamics: Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both. In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for 3 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output. Effects on gastric acid secretion: Misoprostol, over the range of 50–200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion. Uterine effects: Cytotec has been shown to produce uterine contractions that may endanger pregnancy. (See boxed WARNINGS.) Other pharmacologic effects: Cytotec does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Cytotec. Clinical studies: In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70–75% on placebo to 10–30% on misoprostol. Doses of 25–200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding. Reducing the risk of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs): Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Cytotec, 100 mcg of Cytotec, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies. 4 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ........ ........ ........ ........ Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen [No. of patients with ulcer(s) (%)] Therapy Duration Therapy 4 weeks 8 weeks 12 weeks Study No. 1 Cytotec 200 mcg 1 (1.4) 0 0 1 (1.4)* q.i.d. (n=74) Cytotec 100 mcg 3 (3.9) 1 (1.3) 1 (1.3) 5 (6.5)* q.i.d. (n=77) Placebo (n=76) 11 (14.5) 4 (5.3) 4 (5.3) 19 (25.0) Study No. 2 Cytotec 200 mcg 1 (1.5) 1 (1.5) 0 2 (3.1)* q.i.d. (n=65) Cytotec 100 mcg 2 (3.0) 2 (3.0) 1 (1.5) 5 (7.6) q.i.d. (n=66) Placebo (n=62) 6 (9.7) 2 (3.2) 3 (4.8) 11 (17.7) Studies No. 1 & No. 2** Cytotec 200 mcg 2 (1.4) 1 (0.7) 0 3 (2.2)* q.i.d. (n=139) Cytotec 100 mcg 5 (3.5) 3 (2.1) 2 (1.4) 10 (7.0)* q.i.d. (n=143) Placebo (n=138) 17 (12.3) 6 (4.3) 7 (5.1) 30 (21.7) * Statistically significantly different from placebo at the 5% level. ** Combined data from Study No. 1 and Study No. 2. In these trials there were no significant differences between Cytotec and placebo in relief of day or night abdominal pain. No effect of Cytotec in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen. In another clinical trial, 239 patients receiving aspirin 650–1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of Cytotec on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician’s clinical assessment, patient’s assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient’s assessment of pain at rest, movement, interference with daily activity, and ESR. Cytotec did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis. INDICATIONS AND USAGE Cytotec (misoprostol) is indicated for reducing the risk of NSAID (nonsteroidal anti- inflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such 5 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda as patients with a history of ulcer. Cytotec has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Cytotec should be taken for the duration of NSAID therapy. Cytotec has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months’ duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use. CONTRAINDICATIONS See boxed WARNINGS. Cytotec should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Cytotec should not be taken by anyone with a history of allergy to prostaglandins. WARNINGS See boxed WARNINGS. For hospital use only if misoprostol were to be used for cervical ripening, induction of labor, or for the treatment of serious post-partum hemorrhage, which are outside of the approved indication. PRECAUTIONS Caution should be employed when administering Cytotec (misoprostol) to patients with pre-existing cardiovascular disease. Information for patients: Women of childbearing potential using Cytotec to decrease the risk of NSAID-induced ulcers should be told that they must not be pregnant when Cytotec therapy is initiated, and that they must use an effective contraception method while taking Cytotec. See boxed WARNINGS. Cytotec is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. Cytotec should be taken only according to the directions given by a physician. If the patient has questions about or problems with Cytotec, the physician should be contacted promptly. THE PATIENT SHOULD NOT GIVE CYTOTEC TO ANYONE ELSE. Cytotec has been prescribed for the patient’s specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant. 6 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The Cytotec package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Cytotec and each time the prescription is renewed because the leaflet may have been revised. Keep Cytotec out of the reach of children. SPECIAL NOTE FOR WOMEN: Cytotec may cause birth defects, abortion (sometimes incomplete), or premature labor if given to pregnant women. Cytotec is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. Drug interactions: See Clinical Pharmacology. Cytotec has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Cytotec does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Cytotec has no clinically significant effect on the kinetics of diclofenac or ibuprofen. Prostaglandins such as Cytotec may augment the activity of oxytocic agents, especially when given less than 4 hours prior to initiating oxytocin treatment. Concomitant use is not recommended. Animal toxicology: A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Cytotec for up to 1 year. An apparent response of the female mouse to Cytotec in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with Cytotec. Carcinogenesis, mutagenesis, impairment of fertility: There was no evidence of an effect of Cytotec on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of Cytotec on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Cytotec was tested in several in vitro assays, all of which were negative. Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. 7 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Pregnancy Category X. Teratogenic effects: See boxed WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. Cytotec is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic effects: See boxed WARNINGS. Cytotec may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Cytotec may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Cytotec may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID-induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus. Labor and delivery: Cytotec can induce or augment uterine contractions. Vaginal administration of Cytotec, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. A major adverse effect of the obstetrical use of Cytotec is uterine tachysystole which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism and lead to adverse fetal heart changes. Uterine activity and fetal status should be monitored by trained obstetrical personnel in a hospital setting. The risk of uterine rupture increases with advancing gestational ages and prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. The use of Cytotec outside of its approved indication may also be associated with meconium passage, meconium staining of amniotic fluid, and Cesarean delivery. Maternal shock, maternal death, fetal bradycardia, and fetal death have also been reported with the use of misoprostol. Cytotec should not be used in the third trimester in women with a history of Cesarean section or major uterine surgery because of an increased risk of uterine rupture. Cytotec should not be used in cases where uterotonic drugs are generally contraindicated or where hyperstimulation of the uterus is considered inappropriate, such as cephalopelvic disproportion, grand multiparity, hypertonic or hyperactive uterine patterns, or fetal distress where delivery is not imminent, or when surgical intervention is more appropriate. 8 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The effect of Cytotec on later growth, development, and functional maturation of the child when Cytotec is used for cervical ripening or induction of labor has not been established. Information on Cytotec's effect on the need for forceps delivery or other intervention is unknown. Nursing mothers: Misoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol. Caution should be exercised when misoprostol is administered to a nursing woman. Pediatric use: Safety and effectiveness of Cytotec in pediatric patients have not been established. ADVERSE REACTIONS The following have been reported as adverse events in subjects receiving Cytotec: Gastrointestinal: In subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14–40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13–20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Cytotec (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Cytotec is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Cytotec with magnesium-containing antacids. Gynecological: Women who received Cytotec during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Cytotec administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS.) Elderly: There were no significant differences in the safety profile of Cytotec in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. Additional adverse events which were reported are categorized as follows: 9 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Incidence greater than 1%: In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Cytotec and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Cytotec and placebo. Causal relationship unknown: The following adverse events were infrequently reported. Causal relationships between Cytotec and these events have not been established but cannot be excluded: Body as a whole: aches/pains, asthenia, fatigue, fever, chills, rigors, weight changes. Skin: rash, dermatitis, alopecia, pallor, breast pain. Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction (some fatal), thromboembolic events (e.g., pulmonary embolism, arterial thrombosis, and CVA). Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. Hypersensitivity: anaphylactic reaction Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased. OVERDOSAGE The toxic dose of Cytotec in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal 10 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. DOSAGE AND ADMINISTRATION The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology: Clinical studies.) Cytotec should be taken for the duration of NSAID therapy as prescribed by the physician. Cytotec should be taken with a meal, and the last dose of the day should be at bedtime. Renal impairment: Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See Clinical Pharmacology.) HOW SUPPLIED Cytotec 100-mcg tablets are white, round, with SEARLE debossed on one side and 1451 on the other side; supplied as: NDC Number Size 0025-1451-60 unit-of-use bottle of 60 0025-1451-20 unit-of-use bottle of 120 0025-1451-34 carton of 100 unit dose Cytotec 200-mcg tablets are white, hexagonal, with SEARLE debossed above and 1461 debossed below the line on one side and a double stomach debossed on the other side; supplied as: NDC Number Size 0025-1461-60 unit-of-use bottle of 60 0025-1461-31 unit-of-use bottle of 100 0025-1461-34 carton of 100 unit dose Store at or below 25°C (77°F), in a dry area. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com. 11 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0170-3.1 Revised November 2012 Reference ID: 3217917 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda PATIENT INFORMATION Read this leaflet before taking Cytotec® (misoprostol) and each time your prescription is renewed, because the leaflet may be changed. Cytotec (misoprostol) is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take. Do not take Cytotec to reduce the risk of NSAID-induced ulcers if you are pregnant. (See boxed WARNINGS.) Cytotec can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Cytotec has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death. If you become pregnant during Cytotec therapy, stop taking Cytotec and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking Cytotec and contact your physician immediately. Cytotec may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take Cytotec with food. Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take Cytotec. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor. Take Cytotec only according to the directions given by your physician. Do not give Cytotec to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant. This information sheet does not cover all possible side effects of Cytotec. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions. Keep out of reach of children. This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com. 13 Reference ID: 3217917 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo LAB-0172–0.1 Revised September 2012 Reference ID: 3217917 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:19.196872	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019268s047lbl.pdf', 'application_number': 19268, 'submission_type': 'SUPPL ', 'submission_number': 47}
11,464	Cytotec® (misoprostol) WARNINGS CYTOTEC (MISOPROSTOL) ADMINISTRATION TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN CYTOTEC WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY (see also PRECAUTIONS, and LABOR AND DELIVERY). CYTOTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN TO REDUCE THE RISK OF ULCERS INDUCED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS). PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Cytotec should not be used for reducing the risk of NSAID-induced ulcers in women of childbearing potential unless the patient is at high risk of complications from gastric ulcers associated with use of the NSAID, or is at high risk of developing gastric ulceration. In such patients, Cytotec may be prescribed if the patient • has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. • is capable of complying with effective contraceptive measures. • has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. • will begin Cytotec only on the second or third day of the next normal menstrual period. DESCRIPTION Cytotec oral tablets contain either 100 mcg or 200 mcg of misoprostol, a synthetic prostaglandin E1 analog. Misoprostol contains approximately equal amounts of the two diastereomers presented below with their enantiomers indicated by (±): And This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda C22H38O5 M.W. = 382.5 (±) methyl 11{α}//{alpha}, 16-dihydroxy-16-methyl-9- oxoprost-13E-en-1-oate Misoprostol is a water-soluble, viscous liquid. Inactive ingredients of tablets are hydrogenated castor oil, hydroxypropyl methylcellulose, microcrystalline cellulose, and sodium starch glycolate. CLINICAL PHARMACOLOGY Pharmacokinetics: Misoprostol is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F analogs. In normal volunteers, Cytotec (misoprostol) is rapidly absorbed after oral administration with a Tmax of misoprostol acid of 12 ± 3 minutes and a terminal half-life of 20-40 minutes. There is high variability of plasma levels of misoprostol acid between and within studies but mean values after single doses show a linear relationship with dose over the range of 200-400 mcg. No accumulation of misoprostol acid was noted in multiple dose studies; plasma steady state was achieved within two days. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid, however, so this effect does not appear to be clinically important. AUC(0-4) Mean ± SD Cmax(pg/ml) (pg·hr/ml) Tmax(min) Fasting 811 ± 317 417 ± 135 14 ± 8 With Antacid 689 ± 315 349 ± 108* 20 ± 14 With High Fat Breakfast 303 ± 176* 373 ± 111 64 ± 79* * Comparisons with fasting results statistically significant, p<0.05. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda After oral administration of radiolabeled misoprostol, about 80% of detected radioactivity appears in urine. Pharmacokinetic studies in patients with varying degrees of renal impairment showed an approximate doubling of T1/2, Cmax, and AUC compared to normals, but no clear correlation between the degree of impairment and AUC. In subjects over 64 years of age, the AUC for misoprostol acid is increased. No routine dosage adjustment is recommended in older patients or patients with renal impairment, but dosage may need to be reduced if the usual dose is not tolerated. Cytotec does not affect the hepatic mixed function oxidase (cytochrome P-450) enzyme systems in animals. Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically significant. Pharmacokinetic studies also showed a lack of drug interaction with antipyrine and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. Pharmacodynamics: Misoprostol has both antisecretory (inhibiting gastric acid secretion) and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by these agents. Misoprostol can increase bicarbonate and mucus production, but in man this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric ulcer is the result of its antisecretory effect, its mucosal protective effect, or both. In vitro studies on canine parietal cells using tritiated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereospecific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor on intrinsic factor output. Effects on gastric acid secretion: Misoprostol, over the range of 50-200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter lived, and only the 200- mcg dose had substantial effects on nocturnal secretion or on histamine and meal-stimulated secretion. Uterine effects: Cytotec has been shown to produce uterine contractions that may endanger pregnancy. (See boxed WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other pharmacologic effects: Cytotec does not produce clinically significant effects on serum levels of prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin, vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid. Gastric emptying, immunologic competence, platelet aggregation, pulmonary function, or the cardiovascular system are not modified by recommended doses of Cytotec. Clinical studies: In a series of small short-term (about 1 week) placebo-controlled studies in healthy human volunteers, doses of misoprostol were evaluated for their ability to reduce the risk of NSAID- induced mucosal injury. Studies of 200 mcg q.i.d. of misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with ibuprofen, all showed reduction of the rate of significant endoscopic injury from about 70-75% on placebo to 10-30% on misoprostol. Doses of 25-200 mcg q.i.d. reduced aspirin-induced mucosal injury and bleeding. Reducing the risk of gastric ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs): Two 12-week, randomized, double-blind trials in osteoarthritic patients who had gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID compared the ability of 200 mcg of Cytotec, 100 mcg of Cytotec, and placebo to reduce the risk of gastric ulcer (GU) formation. Patients were approximately equally divided between ibuprofen, piroxicam, and naproxen, and continued this treatment throughout the 12 weeks. The 200-mcg dose caused a marked, statistically significant reduction in gastric ulcers in both studies. The lower dose was somewhat less effective, with a significant result in only one of the studies. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reduction of Risk of Gastric Ulcers Induced by Ibuprofen, Piroxicam, or Naproxen [No. of patients with ulcer(s) (%)] Therapy Duration ---------------------------------------- Therapy 4 weeks 8 weeks 12 weeks Study No. 1 Cytotec 200 mcg 1(1.4) 0 0 1(1.4)* q.i.d. (n=74) Cytotec 100 mcg 3(3.9) 1(1.3) 1(1.3) 5(6.5)* q.i.d. (n=77) Placebo (n=76) 11(14.5) 4(5.3) 4(5.3) 19(25.0) Study No. 2 Cytotec 200 mcg 1(1.5) 1(1.5) 0 2(3.1)* q.i.d. (n=65) Cytotec 100 mcg 2(3.0) 2(3.0) 1(1.5) 5(7.6) q.i.d. (n=66) Placebo (n=62) 6(9.7) 2(3.2) 3(4.8) 11(17.7) Studies No. 1 & No. 2** Cytotec 200 mcg 2(1.4) 1(0.7) 0 3(2.2)* q.i.d. (n=139) Cytotec 100 mcg 5(3.5) 3(2.1) 2(1.4) 10(7.0)* q.i.d. (n=143) Placebo (n=138) 17(12.3) 6(4.3) 7(5.1) 30(21.7) Statistically significantly different from placebo at the 5% level. *Combined data from Study No. 1 and Study No. 2. In these trials there were no significant differences between Cytotec and placebo in relief of day or night abdominal pain. No effect of Cytotec in reducing the risk of duodenal ulcers was demonstrated, but relatively few duodenal lesions were seen. In another clinical trial, 239 patients receiving aspirin 650-1300 mg q.i.d. for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8 weeks while continuing to receive aspirin. The study evaluated the possible interference of Cytotec on the efficacy of aspirin in these patients with rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician’s clinical assessment, patient’s assessment, change in ARA classification, change in handgrip strength, change in duration of morning stiffness, patient’s assessment of pain at rest, movement, interference with daily activity, and ESR. Cytotec did not interfere with the efficacy of aspirin in these patients with rheumatoid arthritis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE Cytotec (misoprostol) is indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)-induced gastric ulcers in patients at high risk of complications from gastric ulcer, eg, the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. Cytotec has not been shown to reduce the risk of duodenal ulcers in patients taking NSAIDs. Cytotec should be taken for the duration of NSAID therapy. Cytotec has been shown to reduce the risk of gastric ulcers in controlled studies of 3 months’ duration. It had no effect, compared to placebo, on gastrointestinal pain or discomfort associated with NSAID use. CONTRAINDICATIONS See boxed WARNINGS. Cytotec should not be taken by pregnant women to reduce the risk of ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs). Cytotec should not be taken by anyone with a history of allergy to prostaglandins. WARNINGS See boxed WARNINGS. PRECAUTIONS Information for patients: Women of childbearing potential using Cytotec to decrease the risk of NSAID induced ulcers should be told that they must not be pregnant when Cytotec therapy is initiated, and they must use an effective contraception method while taking Cytotec. See boxed WARNINGS. Cytotec is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer. Cytotec should be taken only according to the directions given by a physician. If the patient has questions about or problems with Cytotec, the physician should be contacted promptly. THE PATIENT SHOULD NOT GIVE CYTOTEC TO ANYONE ELSE. Cytotec has been prescribed for the patient’s specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she is or were to become pregnant. The Cytotec package the patient receives from the pharmacist will include a leaflet containing patient information. The patient should read the leaflet before taking Cytotec and each time the prescription is renewed because the leaflet may have been revised. Keep Cytotec out of the reach of children. SPECIAL NOTE FOR WOMEN: Cytotec may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. Cytotec is available only as a unit-of-use package that includes a leaflet containing patient information. See Patient Information at the end of this labeling. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug interactions: See Clinical Pharmacology. Cytotec has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Cytotec does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of therapeutic doses of aspirin. Cytotec has no clinically significant effect on the kinetics of diclofenac or ibuprofen. Animal toxicology: A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse. No such increase has been observed in humans administered Cytotec for up to 1 year. An apparent response of the female mouse to Cytotec in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long- term studies in the dog and rat and has not been seen in humans treated with Cytotec. Carcinogenesis, mutagenesis, impairment of fertility: There was no evidence of an effect of Cytotec on tumor occurrence or incidence in rats receiving daily doses up to 150 times the human dose for 24 months. Similarly, there was no effect of Cytotec on tumor occurrence or incidence in mice receiving daily doses up to 1000 times the human dose for 21 months. The mutagenic potential of Cytotec was tested in several in vitro assays, all of which were negative. Misoprostol, when administered to breeding male and female rats at doses 6.25 times to 625 times the maximum recommended human therapeutic dose, produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females. Pregnancy: Pregnancy Category X. Teratogenic effects: See boxed WARNINGS. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient but the drug’s teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. Cytotec in not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively. Nonteratogenic effects: See boxed WARNINGS. Cytotec may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Cytotec may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Abortions caused by Cytotec may be incomplete. If a woman is or becomes pregnant while taking this drug to reduce the risk of NSAID induced ulcers, the drug should be discontinued and the patient apprised of the potential hazard to the fetus. Labor and Delivery: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cytotec can induce or augment uterine contractions. Vaginal administration of Cytotec, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony. A major adverse effect of the obstetrical use of Cytotec is hyperstimulation of the uterus which may progress to uterine tetany with marked impairment of uteroplacental blood flow, uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy), or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported. There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of Cytotec; including the manufactured 100 mcg tablet. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. The effect of Cytotec on the later growth, development, and functional maturation of the child when Cytotec is used for cervical ripening or induction of labor have not been established. Information on Cytotec’s effect on the need for forceps delivery or other intervention is unknown. Nursing mothers: It is unlikely that Cytotec is excreted in human milk since it is rapidly metabolized throughout the body. However, it is not known if the active metabolite (misoprostol acid) is excreted in human milk. Therefore, Cytotec should not be administered to nursing mothers because the potential excretion of misoprostol acid could cause significant diarrhea in nursing infants. Pediatric use: Safety and effectiveness of Cytotec in pediatric patients have not been established. ADVERSE REACTIONS The following have been reported as adverse events in subjects receiving Cytotec: Gastrointestinal: In subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14-40% and in all studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13-20% of patients in NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Cytotec (2% of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Cytotec is prescribed. The incidence of diarrhea can be minimized by administering after meals and at bedtime, and by avoiding coadministration of Cytotec with magnesium-containing antacids. Gynecological: Women who received Cytotec during clinical trials reported the following gynecological disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Cytotec administration. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology. (See boxed WARNINGS.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elderly: There were no significant differences in the safety profile of Cytotec in approximately 500 ulcer patients who were 65 years of age or older compared with younger patients. Additional adverse events which were reported are categorized as follows: Incidence greater than 1%: In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving Cytotec and may be causally related to the drug: nausea (3.2%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant differences between the incidences of these events for Cytotec and placebo. Causal relationship unknown: The following adverse events were infrequently reported. Causal relationships between Cytotec and these events have not been established but cannot be excluded: Body as a whole: aches/pains, asthenia, fatigue, fever, rigors, weight changes. Skin: rash, dermatitis, alopecia, pallor, breast pain. Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, increased cardiac enzymes, syncope. Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, amylase increase. Hypersensitivity: anaphylaxis Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased. OVERDOSAGE The toxic dose of Cytotec in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. In animals, the acute toxic effects are diarrhea, gastrointestinal lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy. It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used. (See Clinical Pharmacology: Clinical studies.) Cytotec should be taken for the duration of NSAID therapy as prescribed by the physician. Cytotec should be taken with a meal, and the last dose of the day should be at bedtime. Renal impairment: Adjustment of the dosing schedule in renally impaired patients is not routinely needed, but dosage can be reduced if the 200-mcg dose is not tolerated. (See Clinical Pharmacology.) HOW SUPPLIED Cytotec 100-mcg tablets are white, round, with SEARLE debossed on one side and 1451 on the other side; supplied as: NDC Number Size 0025-1451-60 unit-of-use bottle of 60 0025-1451-20 unit-of-use bottle of 120 0025-1451-34 carton of 100 unit dose Cytotec 200-mcg tablets are white, hexagonal, with SEARLE debossed above and 1461 debossed below the line on one side and a double stomach debossed on the other side; supplied as: NDC Number Size 0025-1461-60 unit-of-use bottle of 60 0025-1461-31 unit-of-use bottle of 100 0025-1461-34 carton of 100 unit dose Store at or below 25°C (77°F), in a dry area. Rx only PATIENT INFORMATION Read this leaflet before taking Cytotec® (misoprostol) and each time your prescription is renewed, because the leaflet may be changed. Cytotec (misoprostol) is being prescribed by your doctor to decrease the chance of getting stomach ulcers related to the arthritis/pain medication that you take. Do not take Cytotec to reduce the risk of NSAID induced ulcers if you are pregnant ( See boxed WARNINGS). Cytotec can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Cytotec has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death. If you become pregnant during Cytotec therapy, stop taking Cytotec and contact your physician immediately. Remember that even if you are on a means of birth control it is still possible to become pregnant. Should this occur, stop taking Cytotec and contact your physician immediately. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cytotec may cause diarrhea, abdominal cramping, and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week. You can minimize possible diarrhea by making sure you take Cytotec with food. Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take Cytotec. If you have prolonged difficulty (more than 8 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor. Take Cytotec only according to the directions given by your physician. Do not give Cytotec to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and would be dangerous if the other person were pregnant. This information sheet does not cover all possible side effects of Cytotec. This patient information leaflet does not address the side effects of your arthritis/pain medication. See your doctor if you have questions. Keep out of reach of children. G.D. Searle & Co. Box 5110, Chicago IL 60680 Address medical inquiries to: G.D. Searle & Co. Healthcare Information Services 5200 Old Orchard Road Skokie IL 60077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:19.275354	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19268slr037.pdf', 'application_number': 19268, 'submission_type': 'SUPPL ', 'submission_number': 37}
11,468	Reference ID: 3788314 March 2015 injection of the entire dose yields peak blood iodine concentrations immediately including close attention to guidewire and catheter manipulation, use of manifold Prior to the injection of any contrast medium, the patient should be questioned to following the injection, which fall rapidly over the next five to ten minutes. This can systems and/or three -way stopcocks, frequent catheter flushing with heparinized obtain a medical histor y with emphasis on allergy and hypersensitivity. A positive be accounted for by the dilution in the vascular and extracellular fluid compartments, saline solutions and minimizing the length of the procedure. The use of plastic history of bronchial asthma or allergy (including food), a family history of allergy, which causes an initial sharp fall in plasma concentration. Equilibration with the syringes in place of glass syringes has been reported to decrease, but not eliminate, or a previous reaction or hypersensitivity to a contrast agent may imply a greater ex tracellular compar tments is reached by about ten minutes; thereaf ter, the fall the likelihood of in vitro clotting. than usual risk. Such a history, by suggesting histamine sensitivity and consequently MD-76™R becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that the contrast enhancement of the Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction. proneness to reac tions, may be more accurate than pretesting in predic ting the potential for reactions, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent when a diagnostic procedure is thought essential, but does call [Diatrizoate Meglumine and image is at least in part dependent on the accumulation of iodine within the lesion Serious neurologic sequelae, including permanent paralysis, have been reported for caution (see ADVERSE REACTIONS). Diatrizoate Sodium Injection USP] and outside the blood pool. In brain scanning, the contrast medium (MD-76R) does not accumulate in normal brain tissue due to the presence of the “blood brain barrier”. The increase in x-ray absorption in the normal brain is due to the presence of the contrast agent within the following injec tions of concentrated contrast media into ar teries supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors, since they strongly potentiate neurologic effects (see PRECAUTIONS pertaining to Aortography). Prophy lac tic therapy including c o r t icost e ro ids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pretest, since the incidence of reaction in these patients is two to three times that of the general population. Adequate doses of blood pool. A break in the blood brain barrier, such as occurs in malignant tumors of I n patients with subarachnoid hemorrhage, a rare association bet ween contrast corticosteroids should be started early enough prior to contrast medium injection, and NOT FOR INTRATHECAL USE the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium. administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated ionic contrast media in for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pretreatment does DESCRIPTION The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool. these patients should be undertaken with caution. A definite risk exists in the use of intravascular contrast agents in patients who are not prevent serious life-threatening reactions, but may reduce both their incidence and severity. A separate syringe should be used for these injections. MD -76R (Diatrizoate Meglumine and Diatrizoate Sodium I njec tion USP) is a known to have multiple myeloma. In such instances, there has been anuria resulting in The possibility of thrombosis should be borne in mind when percutaneous techniques radiopaque contrast agent supplied as a sterile, aqueous solution. Intended CT Scanning of the Body1 progressive uremia, renal failure and eventually death. Although neither the contrast are employed. f or intra v ascular administration, MD -76R c o ntains 66% w/v 1-deo x y -1 (methylamino)-D-glucitol 3,5-diacetamido-2,4,6, triiodobenzoate (salt) and 10% w/v monosodium 3,5-diacetamido-2,4,6, triiodobenzoate. The two salts have the following structural formulae: In non-neural tissues (during C T of the body), MD -76R diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue, since no barrier exists; contrast enhancement is thus due to the agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be the causative factor. The risk in myelomatous patients is not a contraindication to the procedures; however, partial dehydration in the preparation of these patients for the examination is not Consideration must be given to the functional ability of the kidneys before injecting this preparation. General anesthesia may be indicated in the performance of some procedures in young relative differences in extra-vascular diffusion between normal and abnormal tissue, a recommended, since this may predispose to the precipitation of myeloma protein or uncooperative children and in selected adult patients; however, a higher incidence H H OH H situation quite different than that in the brain. in the renal tubules. No form of therapy, including dialysis, has been successful in of adverse reactions has been reported in these patients. This may be attributable reversing this effect. Myeloma, which occurs most commonly in persons over age 40, to the inability of the patient to identify untoward symptoms, or to the hypotensive COOH • HOCH2 C C C C CH2NHCH3 The pharmacokinetics of MD-76R in normal and abnormal tissues has been shown to should be considered before intravascular administration of a contrast agent. effect of anesthesia, which can prolong the circulation time and increase the duration I I OH OH H OH be variable. Enhancement of CT with MD-76R may be of benefit in establishing diagnoses of Administration of radiopaque materials to patients k n own or suspec ted to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the of contact of the contrast agent. Angiography should be avoided whenever possible in patients with hemocystinuria, certain lesions in some sites with greater assurance than is possible with unenhanced physician, the possible benefits of such procedures outweigh the considered risks, because of the risk of inducing thrombosis and embolism. CH3CONH NHCOCH3 C T and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with C T alone or may help to define suspicious lesions seen with unenhanced CT. the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available. Information for Patients Patients receiving iodinated intravascular contrast agents should be instructed to: I CH3-CO-HN I COONa NH-CO-CH3 I Contrast enhancement appears to be greatest within the 30 to 90 seconds after bolus administration of the contrast agent, and after intra-arterial, rather than intravenous, administration. Therefore, the use of a continuous scanning technique (a series of 2 to 3 second scans beginning at the injection–dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions, occasionally revealing more extensive disease. A cyst, or similar non-vascularized lesion, may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; non-vascularized lesions show no change in CT number, whereas vascularized lesions would show an increase. The latter might be benign, malignant or normal, but it Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially. In patients with advanced renal disease, iodinated contrast media should be used with caution, and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure, and recent renal transplant recipients may present an additional risk. 1. Inform your physician if you are pregnant. 2. I nform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disease (see WARNINGS). 3. Inform your physician if you are allergic to any drugs, food or if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS, General). 4. Inform your physician about any other medications you are currently taking, including non-prescription drugs. Each mL provides 660 mg diatrizoate meglumine and 100 mg diatrizoate sodium, 0.125 mg monobasic sodium phosphate as a buffer and 0.11 mg edetate calcium disodium as a sequestering agent. The pH has been adjusted between 6.5 to 7.7 with either a I is unlikely that it would be a cyst, hematoma, or other non-vascularized lesion. Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings. Renal failure has been repor ted in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent, and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients, there should be no fluid restriction and ever y attempt should be made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most impor tant fac tor Drug/Laboratory Test Interactions Iodine-containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g., PBI and radioactive iodine uptake studies. Such tests, if indicated, should be performed prior to the administration of this preparation or delayed for about two weeks following administration. meglumine and sodium hydroxide combination, or diatrizoic acid. Each mL contains influencing further renal impairment. Contrast agents may inter fere with some chemical determinations made on urine approximately 3.65 mg (0.16 mEq) sodium and 370 mg of organically bound iodine. The viscosity of the solution is 16.4 cps at 25°C and 10.5 cps at 37°C. It is hypertonic to blood with an osmolality of 1551 m0sm/Kg. At the time of manufacture, the air in the container is replaced by nitrogen. INDICATIONS AND USAGE MD-76R is indicated in excretion urography, aortography, pediatric angiocardiography, peripheral arteriography, selective renal arteriography, selective visceral arteriography, selec tive coronar y ar teriography with or without left ventriculography, contrast Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible nondiabetic patients (of ten elderly with pre -existing renal disease) following the administration of iodinated contrast agents. Therefore, careful consideration of the potential risks should be given before performing this specimens; therefore, urine should be collected before administration of the contrast medium, or two or more days afterwards. Following selec tive c oronar y ar teriog r aphy, transient elevation of cr eatinine phosphokinase (CPK) has occurred in approximately 30% of patients tested. CLINICAL PHARMACOLOGY enhancement of computed tomographic brain imaging and for intravenous digital subtraction angiography. radiographic procedure in these patients. Caution should be exercised in performing contrast medium studies in patients with Post-arteriographic changes in laboratory studies include transient elevations in BUN, serum creatinine and glucose. Following intra v ascular injec tion, MD -76R is rapidly transpor t ed through the bloodstream to the kidneys and is excreted unchanged in the urine by glomerular filtration. The pharmacokinetics of intravascularly administered radiopaque contrast MD -76R is also indicat ed for the co ntrast enhanc ement in body c omput ed t omograph y ( see CLINIC AL PHARMACOLOGY ). C o ntinuous or multiple scans separated by inter vals of 1 to 3 seconds during the first 30 to 90 seconds post endotoxemia and/or those with elevated body temperatures. Repor ts of thyroid storm occurring following the intravascular use of iodinated radiopaque agents in patients with hyper thyroidism or with an autonomously Hypertonic solutions cause a decrease in hematocrit in vitro and in vivo, and shrinkage of red blood cells. media are usually best described b y a t wo c ompar tment model with a rapid injection of the contrast medium (dynamic C T scanning) provide enhancement of functioning thyroid nodule suggest that this additional risk be evaluated in such Carcinogenesis, Mutagenesis, Impairment of Fertility MD-76™R alpha phase for drug distribution and a slower beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives of MD-76R were approximately 10 and 100 minutes, respectively. Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal passages may begin as early as 5 minutes af ter injec tion. In infants and small children, excretion takes place somewhat more promptly than in adults, so that maximal opacification occurs more rapidly and is less sustained. The normal kidney diagnostic significance. Subsets of patients in whom delayed body C T scans might be helpful have not been identified. Inconsistent results have been repor ted and abnormal and normal tissues may be isodense during the time frame used for delayed CT scanning. The risks of such indiscriminate use of contrast media are well known and such use is not recommended. At present, consistent results have been documented using dynamic CT techniques only. patients before use of this drug. Avoid accidental introduction of this preparation into the subarachnoid space, since even small amounts may produce convulsions and possible fatal reactions. Convulsions have occurred in patients with primar y or metastatic cerebral lesions following administration of contrast media for contrast enhancement of CT brain images. No long-term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females. Pregnancy Category B Diatrizoate sodium and diatrizoate meglumine administered intravenously cross the placenta and are evenly distributed in fetal tissues. No teratogenic effects attributable to [Diatrizoate Meglumine and Diatrizoate Sodium Injection USP] Rx only eliminates the contrast medium almost immediately. I n nephropathic conditions, par ticularly when excretor y capacity has been altered, the rate of excretion varies unpredictably, and opacification may be delayed for 30 minutes or more after injection; with severe impairment, opacification may not occur. Generally, however, the medium is concentrated in sufficient amounts and promptly enough to permit a thorough evaluation of the anatomy and physiology of the urinary tract. Intravascular injection also opacifies those vessels in the path of flow of the medium, permitting visualization until the circulating blood dilutes the concentration of the medium. Thus, selective angiography may be performed following injection directly into veins or arteries. I njec table iodinated contrast agents are excreted either through the k idneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Diatrizoate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys. CONTRAINDICATIONS MD-76R should not be used for myelography. Refer to PRECAUTIONS, General concerning hypersensitivity. WARNINGS SEVERE ADVERSE EVENTS – INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have been repor ted due to the inadver tent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use . T hese serious adv erse r eac tions include: death, c o n vulsions , c e r ebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to ensure that this drug product is not administered intrathecally. PRECAUTIONS General Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions may be minor, life threatening and fatal reactions may occur without warning. The risk-benefit factor should always be carefully evaluated before such a procedure is undertaken. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been k nown to occur, emergenc y facilities and competent personnel should be available for at least 30 to 60 minutes after administration (see ADVERSE REACTIONS). diatrizoate sodium or diatrizoate meglumine have been observed in teratology studies performed in animals. There are, however, no adequate and well-controlled studies in pregnant women. Because animal teratology studies are not always predictive of human response, this agent should be used during pregnancy only if clearly needed. Nursing Mothers Diatrizoate salts are excreted in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug. (Precautions for specific procedures receive comment under that procedure.) ADVERSE REACTIONS Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been repor ted during angiographic Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre -existing renal insufficiency, patients with advanced vascular disease and diabetic patients. Chemotoxic reactions result from the physio-chemical properties of the contrast media, the dose, and speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. Diatrizoate salts cross the placental barrier in humans and are excreted in human milk. procedures with both ionic and nonionic contrast media. Therefore, meticulous Severe reac tions to contrast media of ten resemble allergic responses. This has Idiosyncratic reactions include all other reactions. They occur more frequently in intravascular administration technique is necessary, particularly during angiographic prompted the use of several provocative pretesting methods, none of which can patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent CT Scanning of the Head procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and be relied on to predict severe reactions. No conclusive relationship between severe reac tions and antigen-antibody reac tions or other manifestations of allergy has on the amount of dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reac tions are subdivided into minor, When used for contrast enhancement in computed tomographic brain scanning, the concomitant medications may contribute to the development of thromboembolic been established. The possibility of an idiosyncratic reaction in patients who have intermediate and severe. The minor reactions are self-limited and of short duration; degree of enhancement is directly related to the amount of iodine administered. Rapid events. For these reasons, meticulous angiographic techniques are recommended, previously received a contrast medium without ill effect should always be considered. the severe reactions are life-threatening and treatment is urgent and mandatory. 1 2 3 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPECIMEN Reference ID: 3788314 Fatalities have been repor ted following the administration of iodine -containing Patient Preparation Warning astrocytomas, oligodendrogliomas and gangliomas; ependyomas; medulloblastomas, Usual Dosage contrast agents. Based upon clinical literature, the incidence of death is reported to meningiomas; neuromas; pinealomas; pituitar y adenomas; craniophar yngiomas; Appropriate preparation of the patient is important for optimal visualization. A low I n addition to the general warnings previously described, the inherent risks of MD-76R may be injected either centrally into the superior or inferior range from one in 10,000 (0.01 percent) to less than one in 100,000 (0.001 percent). germinomas; and metastatic lesions. residue diet is recommended for the day preceding the examination and a laxative is ang iocardiog raph y in c y anotic infants and patients with chr onic pulmonar y vena cava, or peripherally into an appropriate arm vein. For central given the evening before the examination, unless contraindicated. emphysema must be weighed against the necessity for per forming this procedure. injections, catheters may be introduced at the antecubital fossa into Nausea, vomiting, flushing, or a generalized feeling of warmth are the reactions seen The usefulness of contrast enhancement for the investigation of the retrobulbar space In pediatric angiocardiography, a dose of 10 to 20 mL may be particularly hazardous either the basilic or cephalic vein or at the leg into the femoral vein most frequently with intravascular injection. Symptoms which may occur include chills, and in cases of low grade or infiltrative glioma has not been demonstrated. Precautions in infants weighing less than 7 kg. This risk is probably significantly increased if and advanced to the distal segment of the corresponding vena cava. fever, sweating, headache, dizziness, pallor, weakness, severe retching and choking, these infants have pre-existing right heart “strain”, right heart failure, and effectively I n cases where lesions have calcified, there is less likelihood of enhancement. wheezing, a rise or fall in blood pressure, facial or conjunctival petechiae, ur ticaria, I n addition to the general precautions previously described, infants and young For peripheral injections, the catheter is introduced at the antecubital decreased or obliterated pulmonary vascular beds. Following therapy, tumors may show decreased or no enhancement. pruritus, rash and other eruptions, edema, cramps, tremors, itching, sneezing and children should not have any fluid restrictions prior to excretory urography. Injection fossa int o an appropriat e size arm vein. I n order t o r educe the lacrimation. Antihistaminic agents may be of benefit; rarely, such reactions may be of MD-76R represents an osmotic load which, if superimposed on increased serum Adverse Reactions Non-Neoplastic Conditions potential for extravasation during peripheral injection, a catheter of severe enough to require discontinuation of dosage. osmolalit y due t o par tial deh y d ration, may mag nify hyper to nic dehydration approximately 20 cm in length should be employed. (see WARNINGS and PRECAUTIONS, General concerning preparatory dehydration). In addition to the adverse reactions previously described, clinical studies in man, and The use of MD-76R may be beneficial in the image enhancement of non-neoplastic Although venous tolerance is usually good, there have been reports of a burning or related animal experiments, have suggested that the hypertonicity of diatrizoate lesions. Cerebral infarctions of recent onset may be better visualized with the contrast Depending on the area to be imaged, the usual dose range is 20 to 60 mL. stinging sensation or numbness, venospasm or venous pain, and partial collapse of Usual Dosage contrast agents produces significant hemodynamic effects, especially in right-sided enhancement, while some infarctions are obscured if contrast media are used. The use Injections may be repeated as necessary. the injected vein. Neutropenia or thrombophlebitis may occur. Tissue necrosis has injec tions. Large volumes of such agents cause a drop in peripheral ar terial and of iodinated contrast media results in contrast enhancement in about 60% of cerebral The dose range for adults is 20 to 40 mL; the usual dose is 20 mL; children require occurred with extravasation. infarctions studied from one to four weeks from the onset of symptoms. Central catheter injections are usually made with a power injector systemic pressures and cardiac output, a rise in pulmonar y arterial and right-hear t proportionately less. Suggested dosages are as follows: with an injection rate of between 10 and 30 mL/second. When making pressures, bradycardia, and regular ectopic beats. Resulting effects on peripheral Severe reactions which may require emergency measures may take the form of a Sites of ac tive infec tion may also be enhanced following co ntrast medium peripheral injections, rates of 12 to 20 mL/second should be used, under 6 months of age 4 mL ar terial and pulmonar y arterial pressures are postulated to be due to mechanical cardiovascular reac tion charac terized by peripheral vasodilatation with resultant administration. depending on the size of the vein. Also, since contrast medium may 6 to 12 months 6 mL blockage of the pulmonary vascular bed and clumping of red cells. hypotension and reflex tachycardia, dyspnea, agitation, confusion, convulsions, and remain in the arm vein for an extended period following injection, it 1 to 2 years 8 mL cyanosis progressing to unconsciousness. Or, the histamine-liberating effect of these Arteriovenous malformations and aneurysms will show contrast enhancement. In the It is suggested that hemodynamic changes be monitored and that pressures considered may be advisable to flush the vein, immediately following injection 2 to 5 years 10 mL compounds may induce an allergic-like reaction, which may range in severity from case of these vascular lesions, the enhancement is probably dependent on the iodine abnormal under roentgenographic conditions be allowed to return to a pre-angiographic with an appropriate volume (20 to 25 mL) of 5% Dextrose in water or 5 to 7 years 12 mL rhinitis or angioneurotic edema to lar yngeal or bronchial spasm or anaphylactoid content of the circulating blood pool. level before continuation of radiopaque injection; this usually takes 15 minutes. normal saline. 8 to 10 years 14 mL shock. Extremely rare cases of disseminated intravascular coagulation resulting in 11 to 15 years 16 mL The opacification of the inferior vermis following contrast medium administration has death have been reported. Usual Dosage resulted in false positive diagnoses in a number of normal studies. HOW SUPPLIED In adults, when the smaller dose has provided inadequate visualization, or when poor Temporary renal shutdown or other nephropathy may occur. The suggested single dose for children under 5 years of age is 10 to 20 mL, depending visualization is anticipated, the 40 mL dose may be given. Patient Preparation MD-76™R Glass Vials/Bottles NDC Number on the size of the child. For children 5 to 10 years of age, single doses of 20 to 30 mL Thyroid function tests indicative of hypothyroidism or transient thyroid suppression 50x50 mL vials 0019-1317-15 are recommended. Doses up to a total of 100 mL have been given safely. No special patient preparation is required for contrast enhancement of C T brain The preparation is given by intravenous injection. If flushing or nausea occur during have been uncommonly reported following iodinated contrast media administration 12x100 mL bottles 0019-1317-07 scanning. However, it is advisable to ensure that patients are well hydrated prior to administration, injection should be slowed or briefly interrupted until the side effects to adult and pediatric patients, including infants. Some patients were treated for 12x200 mL bottles 0019-1317-09 PERIPHERAL ARTERIOGRAPHY examination. have disappeared. hypothyroidism. MD-76R may be injected into the peripheral arterial circulation. Injection is made into Storage: Store below 30°C (86°F). Exposing this product to very cold Usual Dosage I n addition t o the adv erse r eac tions described above , adv erse r eac tions may the femoral or subclavian artery by the percutaneous or operative method. temperatures may result in crystallization of the salt. If this occurs the AORTOGRAPHY sometimes occur as a consequence of the procedure for which the contrast agent The usual dose is 0.6 mL per pound of body weight (1.3 mL/kg), not to exceed 125 mL, container should be brought to room temperature. Shake vigorously Patient Preparation is used. Adverse reac tions in excretion urography have included cardiac arrest, MD-76R may be administered intravenously or intra-arterially by accepted techniques by intravenous administration. In most cases, scanning may be performed immediately to assure complete dissolution of any crystals. The speed of dissolution ventricular fibrillation, anaphylaxis with severe asthmatic reaction, and flushing due to visualize the aorta and its major branches. T he pr oc edur e is normally per f ormed with local or general anesthesia after completion of administration. However, when fast scanning equipment (less than may be increased by heating with circulating warm air. Before use, to generalized vasodilation. In aortography, the risks of procedures include injury to (see PRECAUTIONS, General). Premedication may be employed as indicated. 1 minute) is used, consideration should be given to waiting approximately five minutes examine the product to assure that all solids are redissolved and that Warnings the aorta and neighboring organs, pleural puncture, renal damage including infarction to allow for maximum contrast enhancement. the container and closure have not been damaged. This preparation is and acute tubular necrosis with oliguria and anuria, accidental selective filling of the I n addition t o the warnings previously described, during aor to graphy b y the Precaution sensitive to light and must be protected from strong daylight or direct right renal artery during the translumbar procedure in the presence of pre-existent translumbar technique, extreme care is advised to avoid inadver tent intrathecal exposure to the sun. In addition to the general precautions previously described, hypotension or moderate CONTRAST ENHANCEMENT IN BODY COMPUTED TOMOGRAPHY1 renal disease, retroperitoneal hemorrhage from the translumbar approach, spinal cord injection, since the injection of even small amounts (5 to 7 mL) of the contrast medium decreases in blood pressure seem to occur frequently with intraarterial (brachial) MD -76R may be administered when necessar y to visualize vessels and organs in As with all contrast media, containers should be inspected prior to injury and pathology associated with the syndrome of transverse myelitis, generalized may cause convulsions, permanent sequelae, or fatality. Should the accident occur, injections; therefore, the blood pressure should be monitored during the immediate patients undergoing CT of the chest, abdomen and pelvis. use to ensure that breakage or other damage has not occurred during petechiae, and death following hypotension, arrhythmia, and anaphylactoid reactions. the patient should be placed upright to confine the hyperbaric solution to a low level, ten minutes after injection; this blood pressure change is transient and usually requires shipping and handling. All containers should be inspected for closure Adverse reactions in pediatric angiocardiography have included arrhythmia and death. anesthesia may be required to control convulsions, and if there is evidence of a large no treatment. Extreme caution during injection of the contrast agent is necessary to Patient Preparation integrity. Damaged containers should not be used. During peripheral arteriography, complications have occurred including hemorrhage dose having been administered, a careful cerebrospinal fluid exchange -washout avoid extravasation and fluoroscopy is recommended. This is particularly important in No special patient preparation is required for contrast enhancement in body C T. In from the puncture site, thrombosis of the vessel, and brachial plexus palsy following should be considered. patients with severe arterial disease. patients undergoing abdominal or pelvic examination, opacification of the bowel may axillar y ar ter y injections. During selective coronary ar teriography with or without left REFERENCE be valuable in scan interpretation. ventriculography, most patients will have transient ECG changes. Transient arrhythmias Precautions Adverse Reactions 1Young, S. W., Turner, R. J., Castellino, R. A.: “A strategy for the contrast may occur infrequently. Ventricular fibrillation may result from manipulation of the I n addition to the general precautions previously described, the hazards of In addition to the adverse reactions previously described, since the contrast agent is Precautions enhanc e ment of malig nant tumors using dynamic c o mput er catheter during the procedure or administration of the medium. Other reactions aor tography include those associated with the par ticular technique employed, the given by rapid injection, pain and flushing of the skin may occur. Patients not under tomography and intravascular pharmacokinetics” Radiology, 137:137-147, In addition to the general precaution previously described, it is advisable to ensure may include hypotension, chest pain, and myocardial infarction. Fatalities have been contrast medium and the underlying pathology which warrants the procedure. general anesthesia may experience nausea and vomiting or a transient feeling of October 1980. that patients are adequately hydrated prior to examination. Patient motion, including repor ted. Complications due to the procedure include hemorrhage, thrombosis, warmth. Vascular spasm occurs rarely, as does thrombosis of the vessel and brachial respiration, can markedly aff ec t image qualit y ; therefore, patient cooperation pseudoaneurysms at the puncture site, and dislodgment of arteriosclerotic plaques. In order to prevent the inadver tent injection of a large dose into a branch of the plexus palsy, following axillary artery injection. is essential. The use of an intravascular contrast medium can obscure tumors in Dissection of the coronary vessels and transient sinus arrest have occurred rarely. aorta or intramurally, the position of the catheter tip or needle should be carefully Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals patients undergoing CT evaluation of the liver resulting in a false negative diagnosis. evaluated. A small dose of 1 to 2 mL should be administered to locate the exact site logo and other brands are trademarks of a Mallinckrodt company. Usual Dosage Adverse r eac tions in selec tiv e renal ar t eriog raphy include nausea, vomiting, Dynamic CT scanning is the procedure of choice for malignant tumor enhancement of the needle or catheter tip. Inadvertent direct injection of contrast medium into hypotension and hypertension. For visualization of an entire extremity, a single dose of 20 to 40 mL is suggested; for (see CLINICAL PHARMACOLOGY). brachiocephalic vessels may result in significant slowing of heart rate, peripheral the upper or lower half of the extremity only, 10 to 20 mL is usually sufficient. The dose © 2015 Mallinckrodt. hypotension and severe CNS reactions, including convulsions. Toxic effects may also for children is reduced in proportion to body weight. Usual Dosage OVERDOSAGE be produced if large quantities of contrast medium are injected directly into aor tic branches, such as the renal ar ter y, and repetitive injec tion of the recommended MD-76R may be administered by intravenous bolus injection, by rapid infusion, or by a Overdosage may occur. The adverse effects of overdosage are life -threatening and Manufactured by: Liebel-Flarsheim Company LLC SELECTIVE RENAL ARTERIOGRAPHY clinical dosage may be hazardous. combination of both. affect mainly the pulmonary and cardiovascular system. The symptoms may include Raleigh, NC 27616 Usual Dosage c yanosis, bradycardia, acidosis, pulmonar y hemorrhage, convulsions, coma and Occasional serious neurologic complications, including paraplegia and quadriplegia, For vascular opacification, a bolus injection of 25 to 50 mL may be used, repeated as The usual dose is 5 to 10 mL injected into either or both renal ar teries via femoral cardiac arrest. Treatment of an overdose is directed toward the support of all vital have been repor ted and may be attributable to an excessive dose being injected necessary. When prolonged arterial or venous phase enhancement is required, and for Made in USA ar tery catheterization. This dose may be repeated as necessar y ; doses up to 60 mL functions and prompt institution of symptomatic therapy. into arterial trunks supplying the spinal arteries or to prolonged contact time of the the enhancement of specific lesions, a rapid infusion of 100 mL may be used. have been given. concentrated contrast medium on the CNS tissue. Conditions which can contribute Diatrizoate salts are dialyzable. to prolonged contact time include decreased circulation, aortic occlusions distal to MKR 13170315 SELECTIVE VISCERAL ARTERIOGRAPHY INTRAVENOUS DIGITAL SUBTRACTION ANGIOGRAPHY The intravenous LD50 value of diatrizoate meglumine and diatrizoate sodium (in grams the site of injection, abdominal compression, hypotension, general anesthesia or the Revised 03/15 Usual Dosage Digital subtrac tion angiography (DSA) is a radiographic modalit y which allows of iodine/kilogram body weight) varied from 5.3 to 6.1 g/kg in mice. The LD50 values administration of vasopressors. When these conditions exist or occur, the necessity dynamic imaging of the arterial system following intravenous injection of iodinated decrease as the rate of injection increases. The usual dose for injections into the superior mesenteric artery is 40 mL, with a range of of per forming or continuing the procedure should be carefully evaluated, and the x-ray contrast media through the use of image intensification, enhancement of the 30 to 60 mL; inferior mesenteric artery, usual dose of 15 mL, with a range of 10 to 25 mL; dose and number of repeat injections should be maintained at a minimum, with iodine signal and digital processing of the image data. Temporal subtraction of the celiac artery, usual dose of 40 mL, with a range of 30 to 50 mL; hepatic artery, usual dose DOSAGE AND ADMINISTRATION appropriate intervals between injections. images obtained during the “first arterial pass” of the injected contrast medium from of 25 mL, with a range of 15 to 35 mL; splenic artery, usual dose of 35 mL, with a range of MD-76R should be at body temperature when injected, and may need to be warmed images obtained before and after contrast medium injection yield images which are Severe pain, paresthesia, or peripheral muscle spasm during injection may require 30 to 40 mL. These doses may be repeated as necessary. before use. If kept in a syringe for prolonged periods before injection, it should be devoid of bone and soft tissue. discontinuance of the procedure and a reevaluation of the placement of the catheter protected from exposure to strong light. tip or needle. SELECTIVE CORONARY ARTERIOGRAPHY WITH OR WITHOUT Areas that have been most frequently examined by intravenous DSA are the heart, LEFT VENTRICULOGRAPHY The patient should be instructed to omit the meal that precedes the examination. including co ronar y by -pass g r af ts; the pulmonar y ar t e ries; the ar te ries of the Following catheter procedure, gentle pressure hemostasis is advised, followed by Precautions Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic brachiocephalic circulation; the aor tic arch; the abdominal aor ta and its major observation and immobilization of the limb for several hours to prevent hemorrhage drug, may be administered prior to the examination. branches including the celiac, mesenterics and renal arteries; the iliac arteries; and the from the site of arterial puncture. In addition to the general precautions previously described, it is recommended that this procedure should not be per formed for approximately four weeks following arteries of the extremities. A preliminary film is recommended to check the position of the patient and the x-ray Usual Dosage the diagnosis of myocardial infarction. Mandatory prerequisites to the procedure exposure factors. Patient Preparation are experienced personnel, ECG monitoring apparatus, and adequate facilities for For adults and children over 16 years of age, the usual dose is 15 to 40 mL as a single If a minor reaction occurs during administration, the injection should be slowed or resuscitation and cardioversion. No special patient preparation is required for DSA. However, it is advisable to ensure injection, repeated if indicated. Children require less in proportion to weight. Doses up that patients are well hydrated prior to examination. stopped until the reaction has subsided. If a major reaction occurs, the injection should to a total of 160 mL have been given safely. Patients should be monitored continuously by ECG throughout the procedure. be discontinued immediately. Since the medium is given by rapid injec tion in this procedure, patients should Precautions Usual Dosage Under no circumstances should either cor ticosteroids or antihistamines be mixed be wat ched f or unt o war d r eac tions during the injec tion. Unless general In addition to the general precautions previously described, the risks associated with in the same syringe with the contrast medium because of a potential for chemical anesthesia is emplo ye d, patients should be warned that they ma y f eel some The usual dosage is 4 to 10 mL injected into either coronary artery and repeated as DSA are those usually attendant with catheter procedures, and include intramural incompatibility. transient pain or burning during the injection, followed by a feeling of warmth necessary; doses up to a total of 150 mL have been given. For left ventriculography, injections, vessel dissection and tissue extravasation. Small test injections of contrast immediately af ter ward. the usual dose is 35 to 50 mL injec ted into the lef t ventricles and repeated as medium made under fluoroscopic observation to ensure the catheter tip is properly Parenteral drug products should be inspected visually for par ticulate matter and necessar y. The total dose for combined selective coronary ar teriography and left positioned, and in the case of peripheral placement that the vein is of adequate size, discoloration prior to administration. ventriculography should not exceed 200 mL. will reduce this potential. PEDIATRIC ANGIOCARDIOGRAPHY EXCRETORY UROGRAPHY Ang iocar diog raphy with MD -76R may be per fo rmed by injec tion int o a large CONTRAST ENHANCEMENT OF COMPUTED TOMOGRAPHIC (CT) Patient motion, including respiration and swallowing, can result in marked image Following intravenous injection, MD-76R is rapidly excreted by the kidneys. MD-76R peripheral vein or by direct catheterization of the heart. BRAIN IMAGING degradation, yielding non-diagnostic studies. Therefore, patient cooperation is may be visualized in the renal parenchyma 30 seconds following bolus injection. essential. Patient Preparation Tumors Maximum radiographic density in the calyces and pelves occurs in most instances Adverse Reactions within 3 to 8 minutes after injection. In patients with severe renal impairment, contrast Patients should be prepared in a manner similar to that used for intravenous MD-76R may be useful to enhance the demonstration of the presence and extent of visualization may be substantially delayed. urography. Appropriate preanesthetic medication should be given. cer tain malignancies, such as: gliomas including malignant gliomas, glioblastomas, see section on ADVERSE REACTIONS, General. 5 6 7 8 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SPECIMEN	custom-source	2025-02-12T13:45:19.631575	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019292s010lbl.pdf', 'application_number': 19292, 'submission_type': 'SUPPL ', 'submission_number': 10}
11,467	CYKLOKAPRON® tranexamic acid injection Antifibrinolytic agent DESCRIPTION Each mL of the sterile solution for intravenous injection contains 100 mg tranexamic acid and Water for Injection to 1 mL. FORMULATION Chemical Name: trans-4-(aminomethyl)cyclohexanecarboxylic acid Structural Formula: structural formula Empirical Formula: C8H15NO2 Molecular Weight: 157.2 Tranexamic acid is a white crystalline powder. The aqueous solution for injection has a pH of 6.5 to 8.0. CLINICAL PHARMACOLOGY Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid. Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic acid in a concentration of 1 mg per mL does not aggregate platelets in vitro. Tranexamic acid in concentrations as low as 1 mg per mL can prolong the thrombin time. However, tranexamic acid in concentrations up to 10 mg per mL in blood showed no influence on the platelet count, the coagulation time, or other coagulation factors in whole blood or citrated blood from normal subjects. The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin. After an intravenous dose of 1 g, the plasma concentration time curve shows a triexponential decay with a half-life of about 2 hours for the terminal elimination phase. The initial volume of distribution is about 9 to 12 liters. Urinary excretion is the main route of elimination via glomerular filtration. Overall renal clearance is equal to overall plasma clearance (110 to 116 mL/min), and more than 95% of the dose is excreted in the Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda urine as unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg per kg body weight. An antifibrinolytic concentration of tranexamic acid remains in different tissues for about 17 hours, and in the serum, up to seven or eight hours. Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg per kg to pregnant women is about 30 mg per liter, as high as in the maternal blood. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. In the joint fluid, the same concentration is obtained as in the serum. The biological half-life of tranexamic acid in the joint fluid is about three hours. The concentration of tranexamic acid in a number of other tissues is lower than in blood. In breast milk, the concentration is about one hundredth of the serum peak concentration. Tranexamic acid concentration in cerebrospinal fluid is about one tenth of that of the plasma. The drug passes into the aqueous humor, the concentration being about one tenth of the plasma concentration. Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration. INDICATIONS AND USAGE CYKLOKAPRON Injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. CONTRAINDICATIONS CYKLOKAPRON Injection is contraindicated: 1. In patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see WARNINGS). 2. In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by CYKLOKAPRON in such patients. 3. In patients with active intravascular clotting. 4. In patients with hypersensitivity to tranexamic acid or any of the ingredients. WARNINGS Focal areas of retinal degeneration have developed in cats, dogs, and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground, and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment, particularly in patients receiving tranexamic acid during cardiovascular surgery and in patients inadvertently given tranexamic acid into the neuraxial system. PRECAUTIONS General The dose of CYKLOKAPRON Injection should be reduced in patients with renal insufficiency because of the risk of accumulation. (See DOSAGE AND ADMINISTRATION.) Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with CYKLOKAPRON. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with CYKLOKAPRON. In addition, cases of central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. CYKLOKAPRON should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with CYKLOKAPRON, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. Drug Interactions No studies of interactions between CYKLOKAPRON and other drugs have been conducted. Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic / neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitro and in vivo test systems. There are no clinical data to assess the effects of tranexamic acid on fertility. Pregnancy (Category B) Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery See above under Pregnancy. Nursing Mothers Tranexamic acid is present in the mother’s milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when CYKLOKAPRON is administered to a nursing woman. Pediatric Use The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing CYKLOKAPRON therapy. Geriatric Use Clinical studies of CYKLOKAPRON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined. OVERDOSAGE Cases of overdosage of CYKLOKAPRON have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; neurologic, e.g., visual impairment, convulsions, headache, mental status changes; myoclonus; and rash. DOSAGE AND ADMINISTRATION Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of CYKLOKAPRON intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days. Note: For patients with moderate to severe impaired renal function, the following dosages are recommended: Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Serum Creatinine (μmol/L) Tranexamic Acid I.V. Dosage 120 to 250 (1.36 to 2.83 mg/dL) 10 mg/kg BID 250 to 500 (2.83 to 5.66 mg/dL) 10 mg/kg daily 10 mg/kg every 48 hours >500 (>5.66 mg/dL) or 5 mg/kg every 24 hours For intravenous infusion, CYKLOKAPRON Injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to CYKLOKAPRON Injection. CYKLOKAPRON Injection should NOT be mixed with blood. The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin. HOW SUPPLIED CYKLOKAPRON Injection 100 mg/mL NDC 0013-1114-10 10 x 10 mL ampules STORAGE Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature]. Rx only company logo LAB-0258-6.1 April 2013 Reference ID: 3302179 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:19.645300	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019281s031lbl.pdf', 'application_number': 19281, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,469	NDA 19-297/S-028 Page 3 Pl 7834-23 I Issued 4\2005 PATIENT INFORMATION NOVANTRONE (noe-VAN-trone) mitoxantrone for injection concentrate SERONO For Treating Multiple Sc1erosis Read this information carefully before you start taking NOVOVANTRONE for multiple sclerosis (MS). This information does not take the place of talking with your doctor. Your doctor can tell you more about NOVANTRONE and answer any questions you have about this treatment. NOVANTRONE is used for other conditions besides MS. This 1eaflet has information about using NOVANTRONE specifically for MS. What is the most important in formation I should know about NOVANTRONE? NOVANTRONE can reduce relapses and disability for patients with worsening forms of MS. • NOVANTRONE may damage your heart at any time during therapy or months to years after therapy ends. Heart damage caused by NOVANTRONE can be serious and may cause death. Your doctor will perform certain tests to see that your heart is working normally before you start to take NOVANTRONE. Your doctor will repeat these heart tests before you receive each additional dose. Your doctor wi11 also perform these tests if you have any symptoms of heart problems. Because the risk to your heart may depend on the total amount of NOVANTRONE given, your doctor will limit the number of doses you get. Most patients will reach this limit after about 8 to 12 doses given over 2 to 3 years. After you have reached your limit, you should not receive any additional NOVANTRONE. You and your doctor should both keep track of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 4 how much NOVANTRONE you get. (See the sections “What diagnostic tests will be performed?” and “What are the possible side effects of NOVANTRONE?”) NOVANTRONE can increase your chance of getting an infection. If you begin to have any signs of infection, such as fever, chills, sore throat, cough, pain with urinating, or urinating more often, call your doctor right away. If you have such an infection, it can usually be treated by taking antibiotics. MS and cancer patients treated with NOVANTRONE have an increased risk of developing leukemia. What is NOVANTRONE? NOVANTRONE is a medicine to treat MS patients with secondary (chronic) progressive, progressing relapsing, or worsening relapsing-remitting MS. It is not for treating primary progressive MS. Patients treated with NOVANTRONE may have fewer relapses and keep their mobility longer. Who should not take NOVANTRONE? Women who are pregnant, are trying to become pregnant, or are breastfeeding should not take NOVANTRONE because it may harm the baby. You should use birth control while taking NOVANTRONE to avoid becoming pregnant. Your doctor should also give you a pregnancy test before each dose, and you should know the results of this test before you get each dose of NOVANTRONE. If you plan on getting pregnant, talk with your doctor about stopping the NOVANTRONE treatments. If you do become pregnant, contact your doctor right away. You should not take NOVANTRONE if your doctor finds you have a low number of white blood cells (leukocytes). You should not take NOVANTRONE if our doctor finds heart’s ability to pump blood is decreased. If you are allergic to NOVANTRONE, you should not take it. The active ingredient is mitoxantrone. Ask your doctor about the inactive ingredients. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 5 Your doctor needs to know the following information about you to help decide if NOVANTRONE is right for you. Tell your doctor if you have now or had in the past • heart diseases • treatment with NOVANTRONE • cancer chemotherapy treatment • radiation treatment to the chest area • blood-clotting problems • anemia or low red blood cell counts • low white blood cell counts • unusual or unexpected bleeding • infections • liver disease or problems • any known allergies or sensitivities Also tell your doctor if you take other medicines, including nonprescription medicines and nutritional supplements. How do I take NOVANTRONE? NOVANTRONE is given through a needle placed in a vein in your arm. The dose takes about 5 to 15 minutes to deliver. NOVANTRONE treatment is usually given once every 3 months for about 2 to 3 years (8 to 12 doses). However, this may differ for different patients. What diagnostic tests will be performed? You will need to have regular testing of your heart and blood to help avoid serious side; effects. Before each dose of NOVANTRONE, your doctor will take blood samples to check your blood counts and liver function. Your doctor may also take a blood sample if you begin to have signs of an infection. If you are a woman who is capable of becoming pregnant, even if you were using birth control, you must have a pregnancy test before each NOVANTRONE dose, and you should know the results before you receive each NOVANTRONE dose. To measure possible changes to the heart, you should have regular testing of your heart’s ability to pump blood. This requires taking pictures of your heart using a simple, painless test such as an This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 6 echocardiogram. Your heart should be tested before each dose of NOVANTRONE, or if you show signs of heart problems. You and your doctor should carefully track the total amount of NOVANTRONE you get. Your doctor may stop NOVANTRONE if your tests show that your heart’s ability to pump blood has decreased. If you change doctors, make sure your new doctor knows how much NOVANTRONE you have taken. What should I avoid while taking NOVANTRONE? Women should not become pregnant or breastfeed while taking NOVANTRONE because it may harm the baby. Talk with your doctor about effective birth control. Tell your doctor if you become pregnant. Talk with your doctor about any medicines you currently take and any medicines you plan to start or stop taking. These include prescription and non-prescription medicines and nutritional supplements. Some medicines may affect how NOVANTRONE works. What are the possible side effects of NOVANTRONE? Most side effects of NOVANTRONE are not severe and can normally be treated by your doctor. The most common side effects of NOVANTRONE in patients with MS are nausea, hair thinning, loss of menstrual periods, bladder infections, and mouth sores. The nausea is usually mild and generally lasts for less than 24 hours. A small number of patients treated with NOVANTRONE develop heart problems. Tell your doctor if you have trouble breathing, swelling of your legs or ankles, or uneven or fast heartbeat. NOVANTRONE may cause your white blood cell count to go down, which increases your chance of getting an infection. This risk is greatest within one month after each dose. In addition, NOVANTRONE may cause your platelet count to go down, which increases your chance of bleeding. Cal] your doctor right away if you begin to have fever, chills, sore throat, cough, pain with urination, urination more often, or if you notice any unusual bleeding or bruising. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 7 NOVANTRONE is dark blue in color, so it may turn your urine a blue-green color for a few days after each dose. The white part of your eyes may also have a slight blue color. Other side effects may occur be sure to tell your doctor about any side effects whether or not they are listed here. General advice about prescription medicines Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you have any concerns about NOVANTRONE, ask your doctor. Your doctor can give you information about NOVANTRONE that was written for health care professionals. For more information call MS LifeLines toll free at 1-877-447-3243. Manufactured for: Serono, Inc. Rockland, MA 02370, USA PI 7834-3 Issued 4/2005 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 8 Novantrone mitoxantrone SERONO For injection concentrate April 2005 Dear Healthcare Professional: This letter is sent to you to supplement previously provided information concerning the risks of cardiotoxicity associated with NOVANTRONE (mitoxantrone for injection concentrate) treatment for multiple sclerosis (MS) and also provides supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with NOVANTRONE. Reports received through post-marketing surveillance, have shown that diminished cardiac function may occur early on in the treatment with NOVANTRONE. Therefore, the Product Labeling for NOVANTRONE was updated in March 2005 to state that cardiac monitoring of MS patients should be performed at baseline and prior to administration of every dose of NOVANTRONE. Please refer to the Product Labeling (enclosed) for full prescribing information, including the specific sections on “Boxed Warnings,” “Warnings,” and “Dosage and Administration.” NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). NOVANTRONE is not indicated in the treatment of patients with primary progressive multiple sclerosis. Cardiotoxicity As stated in the Boxed Warning within the Prescribing Information for NOVANTRONE, Use of NOVANTRONE has been associated with cardiotoxicity. Cardiotoxicity can occur at any time during NOVANTRONE therapy, and the risk increases with cumulative dose. Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE or months to years after termination of therapy. All patients should be carefully assessed for cardiac signs and symptoms by history and physical examination prior to start of NOVANTRONE therapy. Baseline evaluation of left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated radionuclide angiography (MUGA) should be performed. Multiple sclerosis patients with a baseline LVEF <50% should not be treated with NOVANTRONE. LVEF should be reevaluated by echocardiogram or MUGA prior to each dose administered to patients with multiple sclerosis. Additional doses of NOVANTRONE should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during NOVANTRONE therapy. Patients with multiple sclerosis should not receive a cumulative dose greater than 140 mg/m2. In cancer patients, the risk of symptomatic congestive heart failure (CHF) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 9 was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. Presence or history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal / pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with NOVANTRONE may occur whether or not cardiac risk factors are present. For additional information see WARNINGS, Cardiac Effects, and DOSAGE AND ADMINISTRATION. As stated in the WARNINGS section, LVEF should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of NOVANTRONE. Multiple sclerosis patients with a baseline LVEF of <50% should not be treated with NOVANTRONE. Subsequent LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop, and prior to all doses administered to multiple sclerosis patients. NOVANTRONE should not be administered to multiple sclerosis patients with an LVEF of <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of >1 40 mg/m2. Secondary Leukemia (AML) As stated in the Boxed Warning within the prescribing Information for NOVANTRONE, Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS patients followed for varying periods of lime, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported. In 1774 patients with breast cancer who received NOVANTRONE concomitant with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see WARNINGS section). Secondary acute myelogenous leukemia (AML) has been reported in cancer patients treated with anthracyclines. NOVANTRONE is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Cases of secondary AML in MS patients treated with NOVANTRONE have been reported in peer-reviewed literature, through the collection of spontaneous reports, and in a prospective observational study (see below). Because the number of MS patients exposed to NOVANTRONE in post-marketing is unknown and because spontaneous reporting of adverse events can be subject to under-reporting it is not possible to determine incidence—or relative risk to an MS patient—of developing secondary AML. The Registry to Evaluate NOVANTRONE Effects in Worsening MS (RENEW) is an ongoing 5-year, post-marketing, observational study involving a cohort of 505 patients with worsening relapsing-remitting, secondary progressive, or progressive-relapsing MS. Since initiation of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-297/S-028 Page 10 patient enrollment in April 2001, there has been one case of secondary AML reported, involving a 52-year-old female with secondary progressive multiple sclerosis. She had received a cumulative total of 72 mg/m2 of NOVANTRONE, in six infusions given from August 2001 to December 2002, when she was noted to be neutropenic, at which time her treatment with NOVANTRONE was stopped. In May 2004, she was noted to have peripheral blasts and bone marrow biopsy confirmed AML. This patient had no other known risk factors for leukemia and no concomitant potentially cytotoxic drugs were listed. Her AML was considered probably related to NOVANTRONE. Since treatment with idarubicin and ara-C, she has been in remission. Based on this case, the incidence rate in this study is increased as compared to a non- exposed matched population. Because of the risk of secondary AML, strict adherence to existing blood cell count monitoring recommendations for patients being treated with NOVANTRONE for MS should be followed with complete blood counts, including platelets, prior to each course of NOVANTRONE and in the event that signs or symptoms of infection develop. NOVANTRONE generally should not be administered to MS patients with neutrophil counts less than 1500 cells/mm3. Also, regular blood cell counts should be monitored after discontinuation of NOVANTRONE therapy. Prescribers are advised to adhere to the monitoring recommendations made in the Prescribing Information and to make a careful risk-benefit assessment of the use of NOVANTRONE in their MS and oncology patients. If you have any questions regarding this important safety information, please contact Serono Medical Information at 1-888-ASK-SERO (1-888-275-7376). Serono is committed to ensuring that NOVANTRONE is used safely and effectively and to providing you with the most current labeling information for NOVANTRONE. Healthcare professionals should report any serious adverse event suspected to be associated with the use of NOVANTRONE or any of Serono’s products to US Product Surveillance at 1-800- 283-8088 extension 5563 or fax to 1-781-681-2961. Alternatively, this information may be reported to the FDA’s MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), by e-mail (www.fda.gov/medwatch), or by postal mail (with the MedWatch form FDA 3500A) to FDA Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD 20852-9787. Yours sincerely, Paul Lammers, M.D., M.Sc. Chief Medical Officer, Serono Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:19.732940	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019297s028lbl.pdf', 'application_number': 19297, 'submission_type': 'SUPPL ', 'submission_number': 28}
11,470	NOVANTRONE® mitoXANTRONE for injection concentrate WARNING NOVANTRONE® (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. NOVANTRONE® should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. (See ADVERSE REACTIONS, General, Cutaneous and DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions). NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration. (See WARNINGS, General) Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE® therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving NOVANTRONE® . Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE® or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative NOVANTRONE dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with NOVANTRONE, prescribers should consider the following: NOVANTRONE mitoXANTRONE for injection 1 All Patients: - All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to start of NOVANTRONE® therapy. - All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated radionuclide angiography (MUGA), MRI, etc.). Multiple Sclerosis Patients: - MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE® . - MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. - MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of NOVANTRONE® should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during NOVANTRONE® therapy. - MS patients should not receive a cumulative NOVANTRONE dose greater than 140 mg/m2. - MS patients should undergo yearly quantitative LVEF evaluation after stopping NOVANTRONE to monitor for late occurring cardiotoxicity. For additional information, see WARNINGS, Cardiac Effects, and DOSAGE AND ADMINISTRATION. Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported. In 1774 patients with breast cancer who received NOVANTRONE® concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment- related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see WARNINGS section). Secondary acute myelogenous leukemia (AML) has been reported in cancer patients treated with anthracyclines. NOVANTRONE® is an anthracenedione, a related drug. NOVANTRONE mitoXANTRONE for injection 2 S tructural Formula The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. DESCRIPTION NOVANTRONE® (mitoxantrone hydrochloride) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is C22H28N4O6•2HCl and the molecular weight is 517.41. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10 anthracenedione dihydrochloride and the structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also NOVANTRONE mitoXANTRONE for injection 3 interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity. NOVANTRONE® has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen pre sentation, as well as the secretion of interferon gamma, TNFα, and IL-2. Pharmacokinetics Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of NOVANTRONE® can be characterized by a three-compartment mode l. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 7 5 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low. In patients administered 15-90 mg/m2 of NOVANTRONE intravenously, there is a linear relationship between dose and the area under the concentration-time curve (A UC). Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin. Metabolism and Elimination Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovere d in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The NOVANTRONE mitoXANTRONE for injection 4 remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. Special Populations Gender The effect of gender on mitoxantrone pharmacokinetics is unknown. Geriatric In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively. Pediatric Mitoxantrone pharmacokinetics in the pediatric population are unknown. Race The effect of race on mitoxantrone pharmacokinetics is unknown. Renal Impairment Mitoxantrone pharmacokinetics in patients with renal impairment are unknown. Hepatic Impairment Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated wi th NOVANTRONE. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required. NOVANTRONE mitoXANTRONE for injection 5 Drug Interactions: In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3 A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity. Pharmacokinetic studies of the interaction of NOVANTRONE with concomita ntly administered medications in humans have not been performed. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. CLINICAL TRIALS Multiple Sclerosis The safety and efficacy of NOVANTRON E in multiple sclerosis were assessed in two randomized, multicenter clinical studies. One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progres sive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDS S is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment. Patients were randomized to receive placebo, 5 mg/m2 NOVANTRONE, or 12 mg/m2 NOVANTRONE administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imagin g (MRI) at NOVANTRONE mitoXANTRONE for injection 6 baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS , Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SN S]) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score). Results of Study 1 are summarized in Table 1. NOVANTRONE mitoXANTRONE for injection 7 T a b l e NR = not reached within 24 months; MRI = magnetic resonance imaging. * Wei-Lachin test. ** Month 24 value minus baseline. ‡ A subset of 110 patients was selected for MRI analysis. MRI results were not available for all patients at all time points. A second randomized, controlled study (Study 2) evaluated NOVANTRONE in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m2 of IV NOVANTRONE plus 1 g of IV MP (n = 21) (NOV + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new NOVANTRONE mitoXANTRONE for injection 8 Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy. The results of this trial are displayed in Table 2. Table 2 Efficacy Results Study 2 MP alone NOV + MP Primary Endpoint (N = 21) (N = 21) p-value Patients (%) without new Gd-enhancing lesions on MRIs (primary endpoint)* 5 (31%) 19 (90%) 0.001 Secondary Endpoints EDSS change (Month 6 minus baseline)* (mean) -0.1 -1.1 0.013 Annualized relapse rate (mean per patient) 3.0 0.7 0.003 Patients (%) without relapses 7 (33%) 14 (67%) 0.031 MP = methylprednisolone; NOV + MP = NOVANTRONE plus methylprednisolone. * Results at Month 6, not including data for 5 withdrawals in the MP alone group. Advanced Hormone-Refractory Prostate Cancer A multicenter Phase 2 trial of NOVANTRONE and low-dose prednisone (N + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was one partial responder and 12 patients with stable disease. However, nine patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity. These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (N + P) to low-dose prednisone alone (P). Eligible patients were required to have metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. NOVANTRONE was administered at a dose of 12 mg/m2 by short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg twice a day. Patients randomized to the prednisone arm were crossed over to the N + P arm if NOVANTRONE mitoXANTRONE for injection 9 they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone. A total of 161 patients were randomized, 80 to the N + P arm and 81 to the P arm. The median NOVANTRONE dose administered was 12 mg/m2 per cycle. The median cumulative NOVANTRONE dose administered was 73 mg/m2 (range of 12 to 212 mg/m2). A primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) was achieved in 29% of patients randomized to N + P compared to 12% of patients randomized to P alone (p = 0.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. A secondary palliative response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response (defined as primary plus secondary responses) was achieved in 38% of patients randomized to N + P compared to 21% of patients randomized to P (p = 0.025). The median duration of primary palliative response for patients randomized to N + P was 7.6 months compared to 2.1 months for patients randomized to P alone (p = 0.0009). The median duration of overall palliative response for patients randomized to N + P was 5.6 months compared to 1.9 months for patients randomized to P alone (p = 0.0004). Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to N + P was 4.4 months compared to 2.3 months for all patients randomized to P alone (p = 0.0001). Median time to death was 11.3 months for all patients on the N + P arm compared to 10.8 months for all patients on P alone (p = 0.2324). Forty-eight patients on the P arm crossed over to receive N + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover NOVANTRONE mitoXANTRONE for injection 10 were significantly worse for patients who crossed over than for those who remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response on N + P after crossover. The median time to death for patients who crossed over to N + P was 12.7 months. The clinical significance of a fall in prostate-specific antigen (PSA) concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two consecutive follow-up assessments after baseline was reported in 33% of all patients randomized to the N + P arm and 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. For example, among the 26 evaluable patients randomized to the N + P arm who had a ≥ 50% reduction in PSA, only 13 had a primary palliative response. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response. Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3 comparative trial of NOVANTRONE plus hydrocortisone (N + H) versus hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Progression at study entry was defined on the basis of progressive symptoms, increases in measurable or osseous disease, or rising PSA levels. NOVANTRONE was administered intravenously at a dose of 14 mg/m2 every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 subjects were randomized, 119 to the N + H arm and 123 to the H arm. There were no differences in survival between the two arms, with a median of 11.1 months in the N + H arm and 12 months in the H arm (p = 0.3298). Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the N + H arm compared with 2 patients (1.6%) randomized to the H arm NOVANTRONE mitoXANTRONE for injection 11 (p = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the N + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (p = 0.0654). Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the N + H arm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the N + H arm over H alone but was not statistically significant. Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5 point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the N + H arm, compared with +8% for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms. Acute Nonlymphocytic Leukemia In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with NOVANTRONE 12 mg/m2 daily for 3 days as a 10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with NOVANTRONE. Patients who had an incomplete antileukemic response received a second induction course in which NOVANTRONE or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates and median survival information for both the U.S. and international multicenter trials are given in Table 3: NOVANTRONE mitoXANTRONE for injection 12 Table 3 Response Rates, Time to Response, and Survival in U.S. and International Trials % Complete Median Time Trial Response (CR) to CR (days) Survival (days) NOV DAUN NOV DAUN NOV DAUN U.S. 63 (62/98) 53 (54/102) 35 42 312 237 International 50 (56/112) 51 (62/123) 36 42 192 230 NOV = NOVANTRONE® + cytarabine DAUN = daunorubicin + cytarabine In these studies, two consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of NOVANTRONE or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. For the U.S. trial, median granulocyte nadirs for patients receiving NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well- controlled prospective, randomized multicenter trials with NOVANTRONE in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred on the NOVANTRONE arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the NOVANTRONE arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred. NOVANTRONE mitoXANTRONE for injection 13 INDICATIONS AND USAGE NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). NOVANTRONE is not indicated in the treatment of patients with primary progressive multiple sclerosis. The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability. NOVANTRONE in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. NOVANTRONE in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. CONTRAINDICATIONS NOVANTRONE is contraindicated in patients who have demonstrated prior hypersensitivity to it. WARNINGS WHEN NOVANTRONE IS USED IN HIGH DOSES (> 14 mg/m2/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT NOVANTRONE BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING NOVANTRONE mitoXANTRONE for injection 14 ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. NOVANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION. General Patients with preexisting myelosuppression as the result of prior drug therapy should not receive NOVANTRONE unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression. The safety of NOVANTRONE (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY). Safety for use by routes other than intravenous administration has not been established. NOVANTRONE is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. NOVANTRONE must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction. Topoisomerase II inhibitors, including NOVANTRONE, have been associated with the development of secondary AML and myelosuppression. Cardiac Effects Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE therapy in such patients should be determined before starting therapy. NOVANTRONE mitoXANTRONE for injection 15 Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with NOVANTRONE. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%. Multiple Sclerosis Changes in cardiac function may occur in patients with multiple sclerosis treated with NOVANTRONE. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving NOVANTRONE, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial. MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of NOVANTRONE therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. NOVANTRONE should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative NOVANTRONE mitoXANTRONE for injection 16 LVEF evaluation after stopping NOVANTRONE to monitor for late-occurring cardiotoxicity. Leukemia Acute congestive heart failure may occasionally occur in patients treated with NOVANTRONE for ANLL. In first-line comparative trials of NOVANTRONE + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease. Hormone-Refractory Prostate Cancer Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with NOVANTRONE. In a randomized comparative trial of NOVANTRONE plus low-dose prednisone vs low- dose prednisone, 7 of 128 patients (5.5 %) treated with NOVANTRONE had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total NOVANTRONE dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2. Among 112 patients evaluable for safety on the NOVANTRONE + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total NOVANTRONE doses administered to these patients is not available. Pregnancy NOVANTRONE may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal NOVANTRONE mitoXANTRONE for injection 17 growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus. Secondary Leukemia Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802) has been observed. Postmarketing cases of secondary AML have also been reported. In 1774 patients with breast cancer who received NOVANTRONE concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment- related AML was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with NOVANTRONE, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years. Secondary AML has also been reported in cancer patients treated with anthracyclines. NOVANTRONE is an anthracenedione, a related drug. The occurrence of refractory secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. NOVANTRONE mitoXANTRONE for injection 18 PRECAUTIONS General Therapy with NOVANTRONE should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation. Systemic infections should be treated concomitantly with or just prior to commencing therapy with NOVANTRONE. Information for Patients NOVANTRONE may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur. Patients should be advised of the signs and symptoms of myelosuppression. Patients with multiple sclerosis should be provided with the Patient Package Insert at the time that the decision is made to treat with NOVANTRONE and prior to and in close temporal proximity to each treatment. In addition, the physician should discuss the issues addressed in the Patient Package Insert with the patient. Laboratory Tests A complete blood count, including platelets, should be obtained prior to each course of NOVANTRONE and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by NOVANTRONE. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy. NOVANTRONE mitoXANTRONE for injection 19 Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Intravenous treatment of rats and mice, once every 21 days for 24 months, with NOVANTRONE resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis). Intravenous treatment of rats, once every 21 days for 12 months with NOVANTRONE resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis). Mutagenesis NOVANTRONE was clastogenic in the in vivo rat bone marrow assay. NOVANTRONE was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. NOVANTRONE was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma). Drug Interactions Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post- marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. Following concurrent administration of NOVANTRONE with corticosteroids, no evidence of drug interactions has been observed. NOVANTRONE mitoXANTRONE for injection 20 Special Populations Hepatic Impairment Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE. NOVANTRONE should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function. Pregnancy Pregnancy Category D (see WARNINGS). Nursing Mothers NOVANTRONE is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from NOVANTRONE, breast feeding should be discontinued before starting treatment. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Multiple Sclerosis: Clinical studies of Novantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with Novantrone in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out. Acute Nonlymphocytic Leukemia: Although definitive studies with Novantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the NOVANTRONE mitoXANTRONE for injection 21 elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy. ADVERSE REACTIONS Multiple Sclerosis NOVANTRONE has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received NOVANTRONE in combination with corticosteroids. In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 NOVANTRONE arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the NOVANTRONE groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea. Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of NOVANTRONE and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m2 group). Of note, alopecia consisted of mild hair thinning. Two of the 127 patients treated with NOVANTRONE in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study. NOVANTRONE mitoXANTRONE for injection 22 Table 4a Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of NOVANTRONE and That Were Numerically Greater Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Preferred Term (N = 64) (N = 65) (N = 62) Nausea 20 55 76 Alopecia 31 38 61 Menstrual disorder * 26 51 61 Amenorrhea * 3 28 43 Upper respiratory tract infection 52 51 53 Urinary tract infection 13 29 32 Stomatitis 8 15 19 Arrhythmia 8 6 18 Diarrhea 11 25 16 Urine abnormal 6 5 11 ECG abnormal 3 5 11 Constipation 6 14 10 Back pain 5 6 8 Sinusitis 2 3 6 Headache 5 6 6 * Percentage of female patients. The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m2 group, and 81% for the 12 mg/m2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m2 patients (tonsillitis, urinary tract infection [two], endometritis). Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either NOVANTRONE dose group, and that were numerically more frequent than in the placebo group. NOVANTRONE mitoXANTRONE for injection 23 Table 4b Laboratory Abnormalities Occurring in ≥ 5% of Patients* on Either Dose of NOVANTRONE and That Were More Frequent Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Event (N = 64) (N = 65) (N = 62) Leukopenia a 0 9 19 Gamma-GT increased 3 3 15 SGOT increased 8 9 8 Granulocytopenia b 2 6 6 Anemia 2 9 6 SGPT increased 3 6 5 * Assessed using World Heath Organization (WHO) toxicity criteria. a. < 4000 cells/mm3 b. < 2000 cells/mm3 There was no difference among treatment groups in the incidence or severity of hemorrhagic events. In Study 2, NOVANTRONE was administered once a month. Clinical adverse events most frequently reported in the NOVANTRONE group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the NOVANTRONE group and numerically more frequent than in the control group. NOVANTRONE mitoXANTRONE for injection 24 Table 5a Adverse Events of Any Intensity Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) Amenorrhea a 0 53 Alopecia 0 33 Nausea 0 29 Asthenia 0 24 Pharyngitis/throat infection 5 19 Gastralgia/stomach burn/epigastric pain 5 14 Aphthosis 0 10 Cutaneous mycosis 0 10 Rhinitis 0 10 Menorrhagia a 0 7 N = NOVANTRONE, MP = methylprednisolone * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. Percentage of female patients. Table 5b Laboratory Abnormalities Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) WBC low a 14 100 ANC low b 10 100 Lymphocytes low 43 95 Hemoglobin low 48 43 Platelets low c 0 33 SGOT high 5 15 SGPT high 10 15 Glucose high 5 10 Potassium low 0 10 N = NOVANTRONE, MP = methylprednisolone. * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. < 4000 cells/mm3 b. < 1500 cells/mm3 c. < 100,000 cells/mm3 Leukopenia and neutropenia were reported in the N +MP group (see Table 5b). Neutropenia occurred within 3 weeks after NOVANTRONE administration and was NOVANTRONE mitoXANTRONE for injection 25 always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons. Leukemia NOVANTRONE has been studied in approximately 600 patients with acute non- lymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of NOVANTRONE + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression. Table 6 summarizes adverse reactions occurring in patients treated with NOVANTRONE + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial. Adverse reactions are presented as major categories and selected examples of clinically significant subcategories. NOVANTRONE mitoXANTRONE for injection 26 Table 6 Adverse Events Occurring in ANLL Patients Receiving NOVANTRONE or Daunorubicin Induction Consolidation [% pts entering induction] NOV DAUN [% pts entering induction] NOV DAUN Event N = 102 N = 102 N = 55 N = 49 Cardiovascular 26 28 11 24 CHF 5 6 0 0 Arrhythmias 3 3 4 4 Bleeding 37 41 20 6 GI 16 12 2 2 Petechiae/ecchymoses 7 9 11 2 Gastrointestinal 88 85 58 51 Nausea/vomiting 72 67 31 31 Diarrhea 47 47 18 8 Abdominal pain 15 9 9 4 Mucositis/stomatitis 29 33 18 8 Hepatic 10 11 14 2 Jaundice 3 8 7 0 Infections 66 73 60 43 UTI 7 2 7 2 Pneumonia 9 7 9 0 Sepsis 34 36 31 18 Fungal infections 15 13 9 6 Renal failure 8 6 0 2 Fever 78 71 24 18 Alopecia 37 40 22 16 Pulmonary 43 43 24 14 Cough 13 9 9 2 Dyspnea 18 20 6 0 CNS 30 30 34 35 Seizures 4 4 2 8 Headache 10 9 13 8 Eye 7 6 2 4 Conjunctivitis 5 1 0 0 NOV = NOVANTRONE, DAUN = daunorubicin. Hormone-Refractory Prostate Cancer Detailed safety information is available for a total of 353 patients with hormone- refractory prostate cancer treated with NOVANTRONE, including 274 patients who received NOVANTRONE in combination with corticosteroids. Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22. NOVANTRONE mitoXANTRONE for injection 27 Table 7 Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22 N + P P (n = 80) (n = 81) Event % % Nausea 61 35 Fatigue 39 14 Alopecia 29 0 Anorexia 25 6 Constipation 16 14 Dyspnea 11 5 Nail bed changes 11 0 Edema 10 4 Systemic infection 10 7 Mucositis 10 0 UTI 9 4 Emesis 9 5 Pain 8 9 Fever 6 3 Hemorrhage/bruise 6 1 Anemia 5 3 Cough 5 0 Decreased LVEF 5 0 Anxiety/depression 5 3 Dyspepsia 5 6 Skin infection 5 3 Blurred vision 3 5 N = NOVANTRONE, P = prednisone. No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients. Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182. NOVANTRONE mitoXANTRONE for injection 28 Table 8 Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 9182 N + H H (n = 112) (n = 113) Event n % n % Decreased WBC 96 87 4 4 Granulocytes/bands 88 79 3 3 Decreased hemoglobin 83 75 42 39 Lymphocytes 78 72 27 25 Pain 45 41 44 39 Platelets 43 39 8 7 Alkaline Phosphatase 41 37 42 38 Malaise/fatigue 37 34 16 14 Hyperglycemia 33 31 32 30 Edema 31 30 15 14 Nausea 28 26 9 8 Anorexia 24 22 16 14 BUN 24 22 22 20 Transaminase 22 20 16 14 Alopecia 20 20 1 1 Cardiac function 19 18 0 0 Infection 18 17 4 4 Weight loss 18 17 13 12 Dyspnea 16 15 9 8 Diarrhea 16 14 4 4 Fever in absence of infection 15 14 7 6 Weight gain 15 14 16 15 Creatinine 14 13 11 10 Other gastrointestinal 13 14 11 11 Vomiting 12 11 6 5 Other neurologic 11 11 5 5 Hypocalcemia 10 10 5 5 Hematuria 9 11 5 6 Hyponatremia 9 9 3 3 Sweats 9 9 2 2 Other liver 8 8 8 8 Stomatitis 8 8 1 1 Cardiac dysrhythmia 7 7 3 3 Hypokalemia 7 7 4 4 Neuro/constipation 7 7 2 2 Neuro/motor 7 7 3 3 Neuro/mood 6 6 2 2 Skin 6 6 4 4 Cardiac ischemia 5 5 1 1 Chills 5 5 0 0 NOVANTRONE mitoXANTRONE for injection 29 Hemorrhage 5 5 3 3 Myalgias/arthralgias 5 5 3 3 Other kidney/bladder 5 5 3 3 Other endocrine 5 6 3 4 Other pulmonary 5 5 3 3 Hypertension 4 4 5 5 Impotence/libido 4 7 2 3 Proteinuria 4 6 2 3 Sterility 3 5 2 3 N= NOVANTRONE, H= hydrocortisone General Allergic Reaction Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely. Cutaneous Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion. Hematologic Topoisomerase II inhibitors, including NOVANTRONE, in combination with other antineoplastic agents, have been associated with the development of acute leukemia (see WARNINGS). Leukemia Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens. Hormone-Refractory Prostate Cancer In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm3, Grade 4 neutropenia (ANC < 500 /mm3) was observed in 54% of patients treated with NOVANTRONE + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m2, Grade 4 neutropenia in 23% of patients NOVANTRONE mitoXANTRONE for injection 30 treated with NOVANTRONE + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving NOVANTRONE + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm3 were noted in 4% and 3% of patients receiving NOVANTRONE + corticosteroids on these trials, and there was one patient death on NOVANTRONE + hydrocortisone due to intracranial hemorrhage after a fall. Gastrointestinal Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy. Cardiovascular Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS) Pulmonary Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included NOVANTRONE. OVERDOSAGE There is no known specific antidote for NOVANTRONE. Accidental overdoses have been reported. Four patients receiving 140-180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression. Although patients with severe renal failure have not been studied, NOVANTRONE is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis. NOVANTRONE mitoXANTRONE for injection 31 DOSAGE AND ADMINISTRATION (See also WARNINGS) Multiple Sclerosis The recommended dosage of NOVANTRONE is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of NOVANTRONE and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with NOVANTRONE NOVANTRONE should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of NOVANTRONE and in the event that signs or symptoms of infection develop. NOVANTRONE generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Hormone-Refractory Prostate Cancer Based on data from two Phase 3 comparative trials of NOVANTRONE plus corticosteroids versus corticosteroids alone, the recommended dosage of NOVANTRONE is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days. Combination Initial Therapy for ANLL in Adults For induction, the recommended dosage is 12 mg/m2 of NOVANTRONE daily on Days 1-3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7. NOVANTRONE mitoXANTRONE for injection 32 Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. NOVANTRONE should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves. Consolidation therapy which was used in two large randomized multicenter trials consisted of NOVANTRONE, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1-5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY) Hepatic Impairment For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment) Preparation and Administration Precautions NOVANTRONE CONCENTRATE MUST BE DILUTED PRIOR TO USE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The dose of NOVANTRONE should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). NOVANTRONE may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE. NOVANTRONE should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that NOVANTRONE not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous NOVANTRONE mitoXANTRONE for injection 33 infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted NOVANTRONE concentrate should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE. Care in the administration of NOVANTRONE will reduce the chance of extravasation. NOVANTRONE should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of NOVANTRONE with the skin, mucous membranes, or eyes. NOVANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of NOVANTRONE extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction. Skin accidentally exposed to NOVANTRONE should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. NOVANTRONE mitoXANTRONE for injection 34 Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-5 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm_vi_2.html. 3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society. HOW SUPPLIED NOVANTRONE® (mitoxantrone for injection concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows: NDC 44087-1520-1 - 10 mL/multidose vial (20 mg) NOVANTRONE® (mitoxantrone for injection concentrate) should be stored between 15°-25°C (59°-77°F). DO NOT FREEZE. Issue Date 08/2008 Manufactured for: EMD Serono, Inc. Rockland, MA 02370 USA NOVANTRONE mitoXANTRONE for injection 35 PI 7834-3 Issued 8/2008 PATIENT INFORMATION NOVANTRONE® (noe-VAN-trone) mitoXANTRONE for injection concentrate logo For Treating Multiple Sclerosis Read this information carefully before you start taking NOVANTRONE for multiple sclerosis (MS). This information does not take the place of talking with your doctor. Your doctor can tell you more about NOVANTRONE and answer any questions you have about this treatment. NOVANTRONE is used for other conditions besides MS. This leaflet has information about using NOVANTRONE specifically for MS. What is the most important information I should know about NOVANTRONE? • NOVANTRONE can reduce relapses and disability for patients with worsening forms of MS. Page 1 NOVANTRONE® PI 7834-3 • NOVANTRONE may damage your heart at any time during therapy or months to years after therapy ends. Heart damage caused by NOVANTRONE can be serious and may cause death. Your doctor will perform certain tests to see that your heart is working normally before you start to take NOVANTRONE. Your doctor will repeat these heart tests before you receive each additional dose and every year after stopping NOVANTRONE. Your doctor will also perform these tests if you have any symptoms of heart problems. Because the risk to your heart may depend on the total amount of NOVANTRONE given, your doctor will limit the number of doses you get. Most patients will reach this limit after about 8 to 12 doses given over 2 to 3 years. After you have reached your limit, you should not receive any additional NOVANTRONE. You and your doctor should both keep track of how much NOVANTRONE you get. (See the sections “What diagnostic tests will be performed?” and “What are the possible side effects of NOVANTRONE?”) • NOVANTRONE can increase your chance of getting an infection. If you begin to have any signs of infection, such as fever, chills, sore throat, cough, pain with urinating, or urinating more often, call your doctor right away. If you have such an infection, it can usually be treated by taking antibiotics. • MS and cancer patients treated with NOVANTRONE have an increased risk of developing leukemia. What is NOVANTRONE? NOVANTRONE is a medicine to treat MS patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS. It is not for treating primary progressive MS. Patients treated with NOVANTRONE may have fewer relapses and keep their mobility longer. Page 2 NOVANTRONE® PI 7834-3 Who should not take NOVANTRONE? Women who are pregnant, are trying to become pregnant, or are breastfeeding should not take NOVANTRONE because it may harm the baby. You should use birth control while taking NOVANTRONE to avoid becoming pregnant. Your doctor should also give you a pregnancy test before each dose, and you should know the results of this test before you get each dose of NOVANTRONE. If you plan on getting pregnant, talk with your doctor about stopping the NOVANTRONE treatments. If you do become pregnant, contact your doctor right away. You should not take NOVANTRONE if your doctor finds you have a low number of white blood cells (leukocytes). You should not take NOVANTRONE if your doctor finds your heart’s ability to pump blood is decreased. If you are allergic to NOVANTRONE, you should not take it. The active ingredient is mitoxantrone. Ask your doctor about the inactive ingredients. Your doctor needs to know the following information about you to help decide if NOVANTRONE is right for you. Tell your doctor if you have now or had in the past: • heart disease • treatment with NOVANTRONE • cancer chemotherapy treatment • radiation treatment to the chest area • blood-clotting problems • anemia or low red blood cell counts • low white blood cell counts • unusual or unexpected bleeding • infections • liver disease or problems • any known allergies or sensitivities Page 3 NOVANTRONE® PI 7834-3 Also tell your doctor if you take other medicines, including nonprescription medicines and nutritional supplements. How do I take NOVANTRONE? NOVANTRONE is given through a needle placed in a vein in your arm. The dose takes about 5 to 15 minutes to deliver. NOVANTRONE treatment is usually given once every 3 months for about 2 to 3 years (8 to 12 doses). However, this may differ for different patients. What diagnostic tests will be performed? You will need to have regular testing of your heart and blood to help avoid serious side effects. Before each dose of NOVANTRONE, your doctor will take blood samples to check your blood counts and liver function. Your doctor may also take a blood sample if you begin to have signs of an infection. If you are a woman who is capable of becoming pregnant, even if you are using birth control, you must have a pregnancy test before each NOVANTRONE dose, and you should know the results before you receive each NOVANTRONE dose. To measure possible changes to the heart, you should have regular electrocardiograms (ECGs) and you should have regular testing of your heart’s ability to pump blood. Measuring your heart’s ability to pump blood requires taking pictures of your heart using a simple, painless test such as an echocardiogram. Your heart should be tested before each dose of NOVANTRONE, or if you show signs of heart problems. You and your doctor should carefully track the total amount of NOVANTRONE you get. Your doctor may stop NOVANTRONE if your tests show that your heart’s ability to Page 4 NOVANTRONE® PI 7834-3 pump blood has decreased. If you change doctors, make sure your new doctor knows how much NOVANTRONE you have taken. What should I avoid while taking NOVANTRONE? • Women should not become pregnant or breastfeed while taking NOVANTRONE because it may harm the baby. Talk with your doctor about effective birth control. Tell your doctor if you become pregnant. • Talk with your doctor about any medicines you currently take and any medicines you plan to start or stop taking. These include prescription and non-prescription medicines and nutritional supplements. Some medicines may affect how NOVANTRONE works. What are the possible side effects of NOVANTRONE? Most side effects of NOVANTRONE are not severe and can normally be treated by your doctor. The most common side effects of NOVANTRONE in patients with MS are nausea, hair thinning, loss of menstrual periods, bladder infections, and mouth sores. The nausea is usually mild and generally lasts for less than 24 hours. A small number of patients treated with NOVANTRONE develop heart problems during treatment or after treatment has stopped. Tell your doctor if you have trouble breathing, swelling of your legs or ankles, or uneven or fast heartbeat. These problems generally happen in people who get a total lifetime dose of more than 12 doses (usually more than 140 mg/m2) of NOVANTRONE, but can also occur at lower lifetime doses. NOVANTRONE may cause your white blood cell count to go down, which increases your chance of getting an infection. This risk is greatest within one month after each dose. In addition, NOVANTRONE may cause your platelet count to go down, which Page 5 NOVANTRONE® PI 7834-3 increases your chance of bleeding. Call your doctor right away if you begin to have fever, chills, sore throat, cough, pain with urination, urination more often, or if you notice any unusual bleeding or bruising. NOVANTRONE is dark blue in color, so it may turn your urine a blue-green color for a few days after each dose. The white part of your eyes may also have a slight blue color. Other side effects may occur. Be sure to tell your doctor about any side effects whether or not they are listed here. General advice about prescription medicines Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. If you have any concerns about NOVANTRONE, ask your doctor. Your doctor can give you information about NOVANTRONE that was written for health care professionals. For more information, call MS LifeLines toll free at 1-877-447-3243. Manufactured for: EMD Serono, Inc. Rockland, MA 02370 USA PI 7834-3 Issued 8/2008 Page 6	custom-source	2025-02-12T13:45:19.863131	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019297s030s031lbl.pdf', 'application_number': 19297, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,474		custom-source	2025-02-12T13:45:20.107340	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/18-998S058_Vasotec_prntlbl.pdf', 'application_number': 19309, 'submission_type': 'SUPPL ', 'submission_number': 23}
11,475	company logo 2 45766F/Revised: May 2013 3 MAGNESIUM SULFATE 4 INJECTION, USP 5 6 50% 7 DESCRIPTION: 8 Magnesium Sulfate Injection, USP 50% is a sterile, nonpyrogenic, concentrated solution of 9 magnesium sulfate heptahydrate in Water for Injection. It is administered by the intravenous 10 (IV) or intramuscular (IM) routes as an electrolyte replenisher or anticonvulsant. Must be 11 diluted before IV use. 12 Each mL contains: Magnesium sulfate heptahydrate 500 mg; Water for Injection q.s. 13 Sulfuric acid and/or sodium hydroxide may have been added for pH adjustment. The pH of a 5% 14 solution is between 5.5 and 7.0. (Osmolarity: 4060 mOsmol/L (calc.); 2.03 mM/mL magnesium 15 sulfate anhydrous; 4.06 mEq/mL magnesium sulfate anhydrous). 16 The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH 17 adjustment) and is intended only for use as a single dose injection. When smaller doses are 18 required the unused portion should be discarded with the entire unit. 19 Magnesium sulfate heptahydrate is chemically designated MgSO4•7H2O, with a 20 molecular weight of 246.47 and occurs as colorless crystals or white powder freely soluble in 21 water. 1 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 CLINICAL PHARMACOLOGY: 2 Magnesium is an important cofactor for enzymatic reactions and plays an important role in 3 neurochemical transmission and muscular excitability. 4 As a nutritional adjunct in hyperalimentation, the precise mechanism of action for 5 magnesium is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/L) may 6 develop as early as three to four days or within weeks. 7 Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching 8 and tremors. Hypocalcemia and hypokalemia often follow low serum levels of magnesium. 9 While there are large stores of magnesium present intracellularly and in the bones of adults, these 10 stores often are not mobilized sufficiently to maintain plasma levels. Parenteral magnesium 11 therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease. 12 Magnesium prevents or controls convulsions by blocking neuromuscular transmission 13 and decreasing the amount of acetylcholine liberated at the end-plate by the motor nerve 14 impulse. Magnesium is said to have a depressant effect on the central nervous system (CNS), 15 but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia 16 or pre-eclampsia. Normal plasma magnesium levels range from 1.5 to 2.5 mEq/L. 17 As plasma magnesium rises above 4 mEq/L, the deep tendon reflexes are first decreased 18 and then disappear as the plasma level approaches 10 mEq/L. At this level respiratory paralysis 19 may occur. Heart block also may occur at this or lower plasma levels of magnesium. Serum 20 magnesium concentrations in excess of 12 mEq/L may be fatal. 21 Magnesium acts peripherally to produce vasodilation. With low doses only flushing and 22 sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral 23 effects of magnesium poisoning are antagonized to some extent by IV administration of calcium. 2 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Pharmacokinetics 2 With IV administration the onset of anticonvulsant action is immediate and lasts about 30 3 minutes. Following IM administration, the onset of action occurs in about one hour and persists 4 for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/L. 5 Magnesium is excreted solely by the kidneys at a rate proportional to the plasma concentration 6 and glomerular filtration. 7 INDICATIONS AND USAGE: 8 Magnesium Sulfate Injection, USP is suitable for replacement therapy in magnesium deficiency, 9 especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in 10 hypocalcemia. In such cases, the serum magnesium level is usually below the lower limit of 11 normal (1.5 to 2.5 mEq/L) and the serum calcium level is normal (4.3 to 5.3 mEq/L) or elevated. 12 In total parenteral nutrition (TPN), magnesium sulfate may be added to the nutrient 13 admixture to correct or prevent hypomagnesemia which can arise during the course of therapy. 14 Magnesium sulfate injection is also indicated for the prevention and control of seizures in 15 pre-eclampsia and eclampsia, respectively. 16 CONTRAINDICATIONS: 17 Parenteral administration of the drug is contraindicated in patients with heart block or 18 myocardial damage. 19 WARNINGS: 20 FETAL HARM: Continuous administration of magnesium sulfate beyond 5 to 7 days to 21 pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. 22 These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of 3 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 1 neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal 2 harm is not known. Magnesium sulfate should be used during pregnancy only if clearly needed. 3 If magnesium sulfate is given for treatment of preterm labor, the woman should be informed that 4 the efficacy and safety of such use have not been established and that use of magnesium sulfate 5 beyond 5 to 7 days may cause fetal abnormalities. 6 7 ALUMINIUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may 8 reach toxic levels with prolonged parenteral administration if kidney function is impaired. 9 Premature neonates are particularly at risk because their kidneys are immature, and they require 10 large amounts of calcium and phosphate solutions, which contain aluminum. 11 Research indicates that patients with impaired kidney function, including premature 12 neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day 13 accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue 14 loading may occur at even lower rates of administration. 15 Parenteral use in the presence of renal insufficiency may lead to magnesium intoxication. 16 IV use in eclampsia should be reserved for immediate control of life-threatening convulsions. 17 PRECAUTIONS: 18 General 19 Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other 20 hypnotics (or systemic anesthetics) are to be given in conjunction with magnesium, their dosage 21 should be adjusted with caution because of additive CNS depressant effects of magnesium. 22 Because magnesium is removed from the body solely by the kidneys, the drug should be 23 used with caution in patients with renal impairment. Urine output should be maintained at a Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 1 level of 100 mL or more during the four hours preceding each dose. Monitoring serum 2 magnesium levels and the patient’s clinical status is essential to avoid the consequences of 3 overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the 4 patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or 5 more/min). When repeated doses of the drug are given parenterally, knee jerk reflexes should be 6 tested before each dose and if they are absent, no additional magnesium should be given until 7 they return. Serum magnesium levels usually sufficient to control convulsions range from 3 to 8 6 mg/100 mL (2.5 to 5 mEq/L). The strength of the deep tendon reflexes begins to diminish 9 when magnesium levels exceed 4 mEq/L. Reflexes may be absent at 10 mEq magnesium/L, 10 where respiratory paralysis is a potential hazard. An injectable calcium salt should be 11 immediately available to counteract the potential hazards of magnesium intoxication in 12 eclampsia. 13 Magnesium sulfate injection (50%) must be diluted to a concentration of 20% or less 14 prior to IV infusion. Rate of administration should be slow and cautious, to avoid producing 15 hypermagnesemia. The 50% solution also should be diluted to 20% or less for IM injection in 16 infants and children. 17 Laboratory Tests 18 Magnesium sulfate injection should not be given unless hypomagnesemia has been confirmed 19 and the serum concentration of magnesium is monitored. The normal serum level is 1.5 to 20 2.5 mEq/L. 21 Drug Interactions 22 CNS Depressants—When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or 23 other CNS depressants are to be given in conjunction with magnesium, their dosage should be Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 1 adjusted with caution because of additive CNS depressant effects of magnesium. CNS 2 depression and peripheral transmission defects produced by magnesium may be antagonized by 3 calcium. 4 Neuromuscular Blocking Agents—Excessive neuromuscular block has occurred in 5 patients receiving parenteral magnesium sulfate and a neuromuscular blocking agent; these drugs 6 should be administered concomitantly with caution. 7 Cardiac Glycosides—Magnesium sulfate should be administered with extreme caution in 8 digitalized patients, because serious changes in cardiac conduction which can result in heart 9 block may occur if administration of calcium is required to treat magnesium toxicity. 10 Pregnancy 11 Teratogenic Effects: 12 Pregnancy Category D (See WARNINGS and PRECAUTIONS) 13 See WARNINGS and PRECAUTIONS. 14 Magnesium sulfate can cause fetal abnormalities when administered beyond 5-7 days to 15 pregnant women. There are retrospective epidemiological studies and case reports documenting 16 fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other 17 skeletal abnormalities with continuous maternal administration of magnesium sulfate for more 18 than 5 to 7 days.1-10 Magnesium sulfate injection should be used during pregnancy only if 19 clearly needed. If this drug is used during pregnancy, the woman should be apprised of the 20 potential harm to the fetus. 21 22 23 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 1 Nonteratogenic Effects: 2 When administered by continuous IV infusion (especially for more than 24 hours preceding 3 delivery) to control convulsions in a toxemic woman, the newborn may show signs of 4 magnesium toxicity, including neuromuscular or respiratory depression (see OVERDOSAGE). 5 Labor and Delivery 6 Continuous administration of magnesium sulfate is an unapproved treatment for preterm labor. 7 The safety and efficacy of such use have not been established. The administration of magnesium 8 sulfate outside of its approved indication in pregnant women should be by trained obstetrical 9 personnel in a hospital setting with appropriate obstetrical care facilities. 10 Nursing Mothers 11 Since magnesium is distributed into milk during parenteral magnesium sulfate administration, 12 the drug should be used with caution in nursing women. 13 Geriatrics 14 Geriatric patients often require reduced dosage because of impaired renal function. In patients 15 with severe impairment, dosage should not exceed 20 g in 48 hours. Serum magnesium should 16 be monitored in such patients. 17 ADVERSE REACTIONS: 18 The adverse effects of parenterally administered magnesium usually are the result of magnesium 19 intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid 20 paralysis, hypothermia, circulatory collapse, cardiac and CNS depression proceeding to 21 respiratory paralysis. Hypocalcemia with signs of tetany secondary to magnesium sulfate 22 therapy for eclampsia has been reported. Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 OVERDOSAGE: 2 Magnesium intoxication is manifested by a sharp drop in blood pressure and respiratory 3 paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of 4 magnesium intoxication. In the event of overdosage, artificial ventilation must be provided until 5 a calcium salt can be injected IV to antagonize the effects of magnesium. 6 For Treatment of Overdose 7 Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution 8 (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of 9 hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful. 10 Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via 11 endotracheal intubation or intermittent positive pressure ventilation as well as IV calcium. 12 DOSAGE AND ADMINISTRATION: 13 Dosage of magnesium sulfate must be carefully adjusted according to individual requirements 14 and response, and administration of the drug should be discontinued as soon as the desired effect 15 is obtained. 16 Both IV and IM administration are appropriate. IM administration of the undiluted 50% 17 solution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a 18 therapeutic level almost immediately. The rate of IV injection should generally not exceed 19 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia 20 with seizures (see below). Continuous maternal administration of magnesium sulfate in 21 pregnancy beyond 5 to 7 days can cause fetal abnormalities. 22 Solutions for IV infusion must be diluted to a concentration of 20% or less prior to 23 administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium 8 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chloride Injection, USP. Deep IM injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children. In Magnesium Deficiency In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary. Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity. In Hyperalimentation In TPN, maintenance requirements for magnesium are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily. In Pre-eclampsia or Eclampsia In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to 9 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 1 four minutes. Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into 2 alternate buttocks every four hours as needed, depending on the continuing presence of the 3 patellar reflex and adequate respiratory function. Alternatively, after the initial IV dose, some 4 clinicians administer 1 to 2 g/hour by constant IV infusion. Therapy should continue until 5 paroxysms cease. A serum magnesium level of 6 mg/100 mL is considered optimal for control 6 of seizures. A total daily (24 hr) dose of 30 to 40 g should not be exceeded. In the presence of 7 severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and 8 frequent serum magnesium concentrations must be obtained. Continuous use of magnesium 9 sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities. 10 Other uses 11 In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of 12 magnesium sulfate is 1 to 2 g given IV. 13 For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, 14 the usual adult dose is 1 g administered IM or IV. 15 In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures 16 have failed and there is no evidence of myocardial damage. The usual dose is 3 to 4 g (30 to 17 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution. 18 For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV. 19 Incompatibilities 20 Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions 21 containing: 22 23 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Alcohol (in high concentrations) Heavy metals Alkali carbonates and bicarbonates Hydrocortisone sodium succinate Alkali hydroxides Phosphates Arsenates Polymyxin B sulfate Barium Procaine hydrochloride Calcium Salicylates Clindamycin phosphate Strontium Tartrates 1 The potential incompatibility will often be influenced by the changes in the concentration 2 of reactants and the pH of the solutions. 3 It has been reported that magnesium may reduce the antibiotic activity of streptomycin, 4 tetracycline and tobramycin when given together. 5 Parenteral drug products should be inspected visually for particulate matter and 6 discoloration prior to administration, whenever solution and container permit. 7 HOW SUPPLIED: Magnesium Product NDC Sulfate Fill Magnesium Sulfate No. No. Heptahydrate Volume mg/mL mg/mL 96402 63323-064-02 500 mg/mL 2 mL 49.3 194.7 96410P 63323-064-10 500 mg/mL 10 mL 49.3 194.7 8 Above products packaged in plastic vials. 9 Product number with a ‘‘P’’ suffix indicates vial is partially filled. 10 Do not administer unless solution is clear and seal is intact. Contains no preservative. 11 Discard unused portion. 11 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. 2 REFERENCES: 3 1. Yokoyama K, Takahashi N, Yada Y. Prolonged maternal magnesium administration and 4 bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12. 5 2. Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by 6 fetal magnesium toxicity. J Perinatol. 2006; 26(6):371-4. 7 3. Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of 8 prolonged course of magnesium sulfate tocolysis. Acta Obstet Gynecol Scan. 9 2006;85(9):1099-103. 10 4. Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received 11 magnesium sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. 12 Epub 2004 Feb 18. 13 5. Matsuda Y, Maeda Y, Ito M, et al. Effect of magnesium sulfate treatment on neonatal bone 14 abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8. 15 6. Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous magnesium 16 sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet 17 Invest. 1997;43(4):236-41. 18 7. Santi MD, Henry GW, Douglas GL. Magnesium sulfate treatment of preterm labor as a cause 19 of abnormal neonatal bone mineralization. J Pediatr Orthop. 1994;14(2):249-53. 20 8. Holcomb WL, Shackelford GD, Petrie RH. Magnesium tocolysis and neonatal bone 21 abnormalities: a controlled study. Obstet Gynecol. 1991; 78(4):611-4. 22 9. Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the 23 neonate. Am J Roentgenol. 1989; 152(5):1071-2. 12 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 1 10. Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with magnesium sulfate 2 infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82. 3 11. McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of magnesium sulfate 4 treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 5 56(5): 595-600. 6 12. Riaz M, Porat R, Brodsky NL, et al. The effects of maternal magnesium sulfate treatment on 7 newborns: a prospective controlled study. J Perinatol. 1998;18(6 pt 1):449-54. 8 company logo 10 11 45766F 12 Revised: May 2013 13 Reference ID: 3315639 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:20.632477	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019316s018lbl.pdf', 'application_number': 19316, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,471	NOVANTRONE® mitoXANTRONE for injection concentrate WARNING NOVANTRONE® (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. NOVANTRONE® should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. (See ADVERSE REACTIONS, General, Cutaneous and DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions). NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration. (See WARNINGS, General) Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE® therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving NOVANTRONE® . Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE® or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative NOVANTRONE dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with NOVANTRONE, prescribers should consider the following: NOVANTRONE mitoXANTRONE for injection 1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda All Patients: - All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to start of NOVANTRONE® therapy. - All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated radionuclide angiography (MUGA), MRI, etc.). Multiple Sclerosis Patients: - MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE® . - MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. - MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of NOVANTRONE® should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during NOVANTRONE® therapy. - MS patients should not receive a cumulative NOVANTRONE dose greater than 140 mg/m2. - MS patients should undergo yearly quantitative LVEF evaluation after stopping NOVANTRONE to monitor for late occurring cardiotoxicity. Secondary Leukemia: NOVANTRONE® therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia. For additional information, see WARNINGS and DOSAGE AND ADMINISTRATION. DESCRIPTION NOVANTRONE® (mitoxantrone hydrochloride) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is C22H28N4O6•2HCl and the molecular weight is 517.41. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free NOVANTRONE mitoXANTRONE for injection 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda str uc tur al formula base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10 anthracenedione dihydrochloride and the structural formula is: NHCH 2CH2NHCH 2CH2OH . 2HCl NHCH 2CH2NHCH 2CH2OH CLINICAL PHARMACOLOGY Mechanism of Action Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity. NOVANTRONE® has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2. Pharmacokinetics Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of NOVANTRONE® can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours NOVANTRONE mitoXANTRONE for injection 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (median approximately 75 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low. In patients administered 15-90 mg/m2 of NOVANTRONE intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC). Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin. Metabolism and Elimination Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. Special Populations Gender The effect of gender on mitoxantrone pharmacokinetics is unknown. Geriatric In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively. Pediatric Mitoxantrone pharmacokinetics in the pediatric population are unknown. NOVANTRONE mitoXANTRONE for injection 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Race The effect of race on mitoxantrone pharmacokinetics is unknown. Renal Impairment Mitoxantrone pharmacokinetics in patients with renal impairment are unknown. Hepatic Impairment Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required. Drug Interactions: In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity. Pharmacokinetic studies of the interaction of NOVANTRONE with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. CLINICAL TRIALS Multiple Sclerosis The safety and efficacy of NOVANTRONE in multiple sclerosis were assessed in two randomized, multicenter clinical studies. One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded NOVANTRONE mitoXANTRONE for injection 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment. Patients were randomized to receive placebo, 5 mg/m2 NOVANTRONE, or 12 mg/m2 NOVANTRONE administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score). Results of Study 1 are summarized in Table 1. NOVANTRONE mitoXANTRONE for injection 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1 Efficacy Results at Month 24 Study 1 Primary Endpoints formula Primary efficacy multivariate analysis* - - - < 0.0001 Primary clinical variables analyzed: EDSS change (mean) Ambulation Index change (mean) Mean number of relapses per patient requiring corticosteroid treatment (adjusted for discontinuation) Months to first relapse requiring corticosteroid treatment (median [1st quartile]) Standard Neurological Status change (mean) 0.23 0.77 1.20 14.2 [6.7] 0.77 – 0.23 0.41 0.73 NR [6.9] – 0.38 – 0.13 0.30 0.40 NR [20.4] – 1.07 0.0194 0.0306 0.0002 0.0004 0.0269 MRI‡ No. of patients with new Gd-enhancing lesions Change in number of T2-weighted lesions, mean (n) 5/32 (16%) 4/37 (11%) 1.94 (32) 0.68 (34) 0/31 0.29 (28) 0.022 0.027 NR = not reached within 24 months; MRI = magnetic resonance imaging. * Wei-Lachin test. ** Month 24 value minus baseline. ‡ A subset of 110 patients was selected for MRI analysis. MRI results were not available for all patients at all time points. A second randomized, controlled study (Study 2) evaluated NOVANTRONE in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m2 of IV NOVANTRONE plus 1 g of IV MP (n = 21) (NOV + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new NOVANTRONE mitoXANTRONE for injection 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy. The results of this trial are displayed in Table 2. Table 2 Efficacy Results Study 2 MP alone NOV + MP Primary Endpoint (N = 21) (N = 21) p-value Patients (%) without new Gd-enhancing lesions on MRIs (primary endpoint)* 5 (31%) 19 (90%) 0.001 Secondary Endpoints EDSS change (Month 6 minus baseline)* (mean) -0.1 -1.1 0.013 Annualized relapse rate (mean per patient) 3.0 0.7 0.003 Patients (%) without relapses 7 (33%) 14 (67%) 0.031 MP = methylprednisolone; NOV + MP = NOVANTRONE plus methylprednisolone. * Results at Month 6, not including data for 5 withdrawals in the MP alone group. Advanced Hormone-Refractory Prostate Cancer A multicenter Phase 2 trial of NOVANTRONE and low-dose prednisone (N + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was one partial responder and 12 patients with stable disease. However, nine patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity. These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (N + P) to low-dose prednisone alone (P). Eligible patients were required to have metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain at study entry. NOVANTRONE was administered at a dose of 12 mg/m2 by short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg twice a day. Patients randomized to the prednisone arm were crossed over to the N + P arm if NOVANTRONE mitoXANTRONE for injection 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone. A total of 161 patients were randomized, 80 to the N + P arm and 81 to the P arm. The median NOVANTRONE dose administered was 12 mg/m2 per cycle. The median cumulative NOVANTRONE dose administered was 73 mg/m2 (range of 12 to 212 mg/m2). A primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) was achieved in 29% of patients randomized to N + P compared to 12% of patients randomized to P alone (p = 0.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. A secondary palliative response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response (defined as primary plus secondary responses) was achieved in 38% of patients randomized to N + P compared to 21% of patients randomized to P (p = 0.025). The median duration of primary palliative response for patients randomized to N + P was 7.6 months compared to 2.1 months for patients randomized to P alone (p = 0.0009). The median duration of overall palliative response for patients randomized to N + P was 5.6 months compared to 1.9 months for patients randomized to P alone (p = 0.0004). Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to N + P was 4.4 months compared to 2.3 months for all patients randomized to P alone (p = 0.0001). Median time to death was 11.3 months for all patients on the N + P arm compared to 10.8 months for all patients on P alone (p = 0.2324). Forty-eight patients on the P arm crossed over to receive N + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover NOVANTRONE mitoXANTRONE for injection 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda were significantly worse for patients who crossed over than for those who remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response on N + P after crossover. The median time to death for patients who crossed over to N + P was 12.7 months. The clinical significance of a fall in prostate-specific antigen (PSA) concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two consecutive follow-up assessments after baseline was reported in 33% of all patients randomized to the N + P arm and 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. For example, among the 26 evaluable patients randomized to the N + P arm who had a ≥ 50% reduction in PSA, only 13 had a primary palliative response. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response. Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3 comparative trial of NOVANTRONE plus hydrocortisone (N + H) versus hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Progression at study entry was defined on the basis of progressive symptoms, increases in measurable or osseous disease, or rising PSA levels. NOVANTRONE was administered intravenously at a dose of 14 mg/m2 every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 subjects were randomized, 119 to the N + H arm and 123 to the H arm. There were no differences in survival between the two arms, with a median of 11.1 months in the N + H arm and 12 months in the H arm (p = 0.3298). Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the N + H arm compared with 2 patients (1.6%) randomized to the H arm NOVANTRONE mitoXANTRONE for injection 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (p = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the N + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (p = 0.0654). Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the N + H arm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the N + H arm over H alone but was not statistically significant. Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5 point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the N + H arm, compared with +8% for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms. Acute Nonlymphocytic Leukemia In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with NOVANTRONE 12 mg/m2 daily for 3 days as a 10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with NOVANTRONE. Patients who had an incomplete antileukemic response received a second induction course in which NOVANTRONE or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates and median survival information for both the U.S. and international multicenter trials are given in Table 3: NOVANTRONE mitoXANTRONE for injection 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3 Response Rates, Time to Response, and Survival in U.S. and International Trials % Complete Median Time Trial Response (CR) to CR (days) Survival (days) NOV DAUN NOV DAUN NOV DAUN U.S. 63 (62/98) 53 (54/102) 35 42 312 237 International 50 (56/112) 51 (62/123) 36 42 192 230 NOV = NOVANTRONE® + cytarabine DAUN = daunorubicin + cytarabine In these studies, two consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of NOVANTRONE or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. For the U.S. trial, median granulocyte nadirs for patients receiving NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well- controlled prospective, randomized multicenter trials with NOVANTRONE in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred on the NOVANTRONE arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the NOVANTRONE arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred. NOVANTRONE mitoXANTRONE for injection 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). NOVANTRONE is not indicated in the treatment of patients with primary progressive multiple sclerosis. The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability. NOVANTRONE in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. NOVANTRONE in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. CONTRAINDICATIONS NOVANTRONE is contraindicated in patients who have demonstrated prior hypersensitivity to it. WARNINGS WHEN NOVANTRONE IS USED IN HIGH DOSES (> 14 mg/m2/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT NOVANTRONE BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING NOVANTRONE mitoXANTRONE for injection 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. NOVANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION. General Patients with preexisting myelosuppression as the result of prior drug therapy should not receive NOVANTRONE unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression. The safety of NOVANTRONE (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY). Safety for use by routes other than intravenous administration has not been established. NOVANTRONE is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. NOVANTRONE must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction. Topoisomerase II inhibitors, including NOVANTRONE, have been associated with the development of secondary acute myeloid leukemia and myelosuppression. Cardiac Effects Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE therapy in such patients should be determined before starting therapy. NOVANTRONE mitoXANTRONE for injection 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with NOVANTRONE. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%. Multiple Sclerosis Changes in cardiac function may occur in patients with multiple sclerosis treated with NOVANTRONE. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving NOVANTRONE, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial. MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of NOVANTRONE therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. NOVANTRONE should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative NOVANTRONE mitoXANTRONE for injection 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LVEF evaluation after stopping NOVANTRONE to monitor for late-occurring cardiotoxicity. Leukemia Acute congestive heart failure may occasionally occur in patients treated with NOVANTRONE for ANLL. In first-line comparative trials of NOVANTRONE + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease. Hormone-Refractory Prostate Cancer Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with NOVANTRONE. In a randomized comparative trial of NOVANTRONE plus low-dose prednisone vs low- dose prednisone, 7 of 128 patients (5.5 %) treated with NOVANTRONE had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total NOVANTRONE dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2. Among 112 patients evaluable for safety on the NOVANTRONE + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total NOVANTRONE doses administered to these patients is not available. Pregnancy NOVANTRONE may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal NOVANTRONE mitoXANTRONE for injection 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus. Secondary Leukemia NOVANTRONE® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis. In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup. In a prospective, open-label, tolerability and safety monitoring study of NOVANTRONE® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with NOVANTRONE® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia. In 1774 patients with breast cancer who received NOVANTRONE concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment- related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated NOVANTRONE mitoXANTRONE for injection 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with NOVANTRONE, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years. Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. NOVANTRONE is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections. PRECAUTIONS General Therapy with NOVANTRONE should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation. Systemic infections should be treated concomitantly with or just prior to commencing therapy with NOVANTRONE. Information for Patients NOVANTRONE may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur. Patients should be advised of the signs and symptoms of myelosuppression. Patients with multiple sclerosis should be provided with the Patient Package Insert at the time that the decision is made to treat with NOVANTRONE and prior to and in close temporal proximity to each treatment. In addition, the physician should discuss the issues addressed in the Patient Package Insert with the patient. NOVANTRONE mitoXANTRONE for injection 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Laboratory Tests A complete blood count, including platelets, should be obtained prior to each course of NOVANTRONE and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by NOVANTRONE. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy. Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Intravenous treatment of rats and mice, once every 21 days for 24 months, with NOVANTRONE resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis). Intravenous treatment of rats, once every 21 days for 12 months with NOVANTRONE resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis). Mutagenesis NOVANTRONE was clastogenic in the in vivo rat bone marrow assay. NOVANTRONE was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. NOVANTRONE was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma). NOVANTRONE mitoXANTRONE for injection 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post- marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. Following concurrent administration of NOVANTRONE with corticosteroids, no evidence of drug interactions has been observed. Special Populations Hepatic Impairment Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE. NOVANTRONE should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function. Pregnancy Pregnancy Category D (see WARNINGS). Nursing Mothers NOVANTRONE is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from NOVANTRONE, breast feeding should be discontinued before starting treatment. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Multiple Sclerosis: Clinical studies of Novantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger NOVANTRONE mitoXANTRONE for injection 20 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with Novantrone in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out. Acute Nonlymphocytic Leukemia: Although definitive studies with Novantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy. ADVERSE REACTIONS Multiple Sclerosis NOVANTRONE has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received NOVANTRONE in combination with corticosteroids. In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 NOVANTRONE arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the NOVANTRONE groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea. Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of NOVANTRONE and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in NOVANTRONE mitoXANTRONE for injection 21 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda more than one patient (three patients [5%] in the 12 mg/m2 group). Of note, alopecia consisted of mild hair thinning. Two of the 127 patients treated with NOVANTRONE in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study. Table 4a Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of NOVANTRONE and That Were Numerically Greater Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Preferred Term (N = 64) (N = 65) (N = 62) Nausea 20 55 76 Alopecia 31 38 61 Menstrual disorder * 26 51 61 Amenorrhea * 3 28 43 Upper respiratory tract infection 52 51 53 Urinary tract infection 13 29 32 Stomatitis 8 15 19 Arrhythmia 8 6 18 Diarrhea 11 25 16 Urine abnormal 6 5 11 ECG abnormal 3 5 11 Constipation 6 14 10 Back pain 5 6 8 Sinusitis 2 3 6 Headache 5 6 6 * Percentage of female patients. The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m2 group, and 81% for the 12 mg/m2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m2 patients (tonsillitis, urinary tract infection [two], endometritis). NOVANTRONE mitoXANTRONE for injection 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either NOVANTRONE dose group, and that were numerically more frequent than in the placebo group. Table 4b Laboratory Abnormalities Occurring in ≥ 5% of Patients* on Either Dose of NOVANTRONE and That Were More Frequent Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Event (N = 64) (N = 65) (N = 62) Leukopenia a 0 9 19 Gamma-GT increased 3 3 15 SGOT increased 8 9 8 Granulocytopenia b 2 6 6 Anemia 2 9 6 SGPT increased 3 6 5 * Assessed using World Heath Organization (WHO) toxicity criteria. a. < 4000 cells/mm3 b. < 2000 cells/mm3 There was no difference among treatment groups in the incidence or severity of hemorrhagic events. In Study 2, NOVANTRONE was administered once a month. Clinical adverse events most frequently reported in the NOVANTRONE group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the NOVANTRONE group and numerically more frequent than in the control group. NOVANTRONE mitoXANTRONE for injection 23 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5a Adverse Events of Any Intensity Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) Amenorrhea a 0 53 Alopecia 0 33 Nausea 0 29 Asthenia 0 24 Pharyngitis/throat infection 5 19 Gastralgia/stomach burn/epigastric pain 5 14 Aphthosis 0 10 Cutaneous mycosis 0 10 Rhinitis 0 10 Menorrhagia a 0 7 N = NOVANTRONE, MP = methylprednisolone * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. Percentage of female patients. Table 5b Laboratory Abnormalities Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) WBC low a 14 100 ANC low b 10 100 Lymphocytes low 43 95 Hemoglobin low 48 43 Platelets low c 0 33 SGOT high 5 15 SGPT high 10 15 Glucose high 5 10 Potassium low 0 10 N = NOVANTRONE, MP = methylprednisolone. * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. < 4000 cells/mm3 b. < 1500 cells/mm3 c. < 100,000 cells/mm3 Leukopenia and neutropenia were reported in the N +MP group (see Table 5b). Neutropenia occurred within 3 weeks after NOVANTRONE administration and was NOVANTRONE mitoXANTRONE for injection 24 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons. Leukemia NOVANTRONE has been studied in approximately 600 patients with acute non- lymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of NOVANTRONE + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression. Table 6 summarizes adverse reactions occurring in patients treated with NOVANTRONE + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial. Adverse reactions are presented as major categories and selected examples of clinically significant subcategories. NOVANTRONE mitoXANTRONE for injection 25 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 6 Adverse Events Occurring in ANLL Patients Receiving NOVANTRONE or Daunorubicin Induction Consolidation [% pts entering induction] NOV DAUN [% pts entering induction] NOV DAUN Event N = 102 N = 102 N = 55 N = 49 Cardiovascular 26 28 11 24 CHF 5 6 0 0 Arrhythmias 3 3 4 4 Bleeding 37 41 20 6 GI 16 12 2 2 Petechiae/ecchymoses 7 9 11 2 Gastrointestinal 88 85 58 51 Nausea/vomiting 72 67 31 31 Diarrhea 47 47 18 8 Abdominal pain 15 9 9 4 Mucositis/stomatitis 29 33 18 8 Hepatic 10 11 14 2 Jaundice 3 8 7 0 Infections 66 73 60 43 UTI 7 2 7 2 Pneumonia 9 7 9 0 Sepsis 34 36 31 18 Fungal infections 15 13 9 6 Renal failure 8 6 0 2 Fever 78 71 24 18 Alopecia 37 40 22 16 Pulmonary 43 43 24 14 Cough 13 9 9 2 Dyspnea 18 20 6 0 CNS 30 30 34 35 Seizures 4 4 2 8 Headache 10 9 13 8 Eye 7 6 2 4 Conjunctivitis 5 1 0 0 NOV = NOVANTRONE, DAUN = daunorubicin. Hormone-Refractory Prostate Cancer Detailed safety information is available for a total of 353 patients with hormone- refractory prostate cancer treated with NOVANTRONE, including 274 patients who received NOVANTRONE in combination with corticosteroids. Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22. NOVANTRONE mitoXANTRONE for injection 26 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7 Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22 N + P P (n = 80) (n = 81) Event % % Nausea 61 35 Fatigue 39 14 Alopecia 29 0 Anorexia 25 6 Constipation 16 14 Dyspnea 11 5 Nail bed changes 11 0 Edema 10 4 Systemic infection 10 7 Mucositis 10 0 UTI 9 4 Emesis 9 5 Pain 8 9 Fever 6 3 Hemorrhage/bruise 6 1 Anemia 5 3 Cough 5 0 Decreased LVEF 5 0 Anxiety/depression 5 3 Dyspepsia 5 6 Skin infection 5 3 Blurred vision 3 5 N = NOVANTRONE, P = prednisone. No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients. Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182. NOVANTRONE mitoXANTRONE for injection 27 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 8 Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 9182 N + H H (n = 112) (n = 113) Event n % n % Decreased WBC 96 87 4 4 Abnormal granulocytes/bands 88 79 3 3 Decreased hemoglobin 83 75 42 39 Abnormal lymphocytes count 78 72 27 25 Pain 45 41 44 39 Abnormal platelet count 43 39 8 7 Abnormal alkaline phosphatase 41 37 42 38 Malaise/fatigue 37 34 16 14 Hyperglycemia 33 31 32 30 Edema 31 30 15 14 Nausea 28 26 9 8 Anorexia 24 22 16 14 Abnormal BUN 24 22 22 20 Abnormal Transaminase 22 20 16 14 Alopecia 20 20 1 1 Abnormal Cardiac function 19 18 0 0 Infection 18 17 4 4 Weight loss 18 17 13 12 Dyspnea 16 15 9 8 Diarrhea 16 14 4 4 Fever in absence of infection 15 14 7 6 Weight gain 15 14 16 15 Abnormal creatinine 14 13 11 10 Other gastrointestinal 13 14 11 11 Vomiting 12 11 6 5 Other neurologic 11 11 5 5 Hypocalcemia 10 10 5 5 Hematuria 9 11 5 6 Hyponatremia 9 9 3 3 Sweats 9 9 2 2 Other liver 8 8 8 8 Stomatitis 8 8 1 1 Cardiac dysrhythmia 7 7 3 3 Hypokalemia 7 7 4 4 Neuro/constipation 7 7 2 2 Neuro/motor disorder 7 7 3 3 Neuro/mood disorder 6 6 2 2 Skin disorder 6 6 4 4 Cardiac ischemia 5 5 1 1 Chills 5 5 0 0 NOVANTRONE mitoXANTRONE for injection 28 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemorrhage 5 5 3 3 Myalgias/arthralgias 5 5 3 3 Other kidney/bladder 5 5 3 3 Other endocrine 5 6 3 4 Other pulmonary 5 5 3 3 Hypertension 4 4 5 5 Impotence/libido 4 7 2 3 Proteinuria 4 6 2 3 Sterility 3 5 2 3 N= NOVANTRONE, H= hydrocortisone General Allergic Reaction Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely. Cutaneous Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion. Hematologic Topoisomerase II inhibitors, including NOVANTRONE, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see WARNINGS). Leukemia Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens. Hormone-Refractory Prostate Cancer In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm3, Grade 4 neutropenia (ANC < 500 /mm3) was observed in 54% of patients treated with NOVANTRONE + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m2, Grade 4 neutropenia in 23% of patients NOVANTRONE mitoXANTRONE for injection 29 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treated with NOVANTRONE + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving NOVANTRONE + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm3 were noted in 4% and 3% of patients receiving NOVANTRONE + corticosteroids on these trials, and there was one patient death on NOVANTRONE + hydrocortisone due to intracranial hemorrhage after a fall. Gastrointestinal Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy. Cardiovascular Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS) Pulmonary Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included NOVANTRONE. OVERDOSAGE There is no known specific antidote for NOVANTRONE. Accidental overdoses have been reported. Four patients receiving 140-180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression. Although patients with severe renal failure have not been studied, NOVANTRONE is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis. NOVANTRONE mitoXANTRONE for injection 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION (See also WARNINGS) Multiple Sclerosis The recommended dosage of NOVANTRONE is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of NOVANTRONE and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with NOVANTRONE NOVANTRONE should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of NOVANTRONE and in the event that signs or symptoms of infection develop. NOVANTRONE generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Hormone-Refractory Prostate Cancer Based on data from two Phase 3 comparative trials of NOVANTRONE plus corticosteroids versus corticosteroids alone, the recommended dosage of NOVANTRONE is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days. Combination Initial Therapy for ANLL in Adults For induction, the recommended dosage is 12 mg/m2 of NOVANTRONE daily on Days 1-3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7. NOVANTRONE mitoXANTRONE for injection 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. NOVANTRONE should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves. Consolidation therapy which was used in two large randomized multicenter trials consisted of NOVANTRONE, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1-5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY) Hepatic Impairment For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment) Preparation and Administration Precautions NOVANTRONE CONCENTRATE MUST BE DILUTED PRIOR TO USE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The dose of NOVANTRONE should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). NOVANTRONE may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE. NOVANTRONE should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that NOVANTRONE not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous NOVANTRONE mitoXANTRONE for injection 32 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted NOVANTRONE concentrate should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE. Care in the administration of NOVANTRONE will reduce the chance of extravasation. NOVANTRONE should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of NOVANTRONE with the skin, mucous membranes, or eyes. NOVANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of NOVANTRONE extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction. Skin accidentally exposed to NOVANTRONE should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. NOVANTRONE mitoXANTRONE for injection 33 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-5 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm_vi_2.html. 3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society. HOW SUPPLIED NOVANTRONE® (mitoxantrone for injection concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows: NDC 44087-1520-1 - 20 mg/10 mL/multidose vial (2 mg/mL) NOVANTRONE® (mitoxantrone for injection concentrate) should be stored between 15°-25°C (59°-77°F). DO NOT FREEZE. Issue Date: May/2010 Manufactured for: EMD Serono, Inc. Rockland, MA 02370 USA NOVANTRONE mitoXANTRONE for injection 34 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:20.685703	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019297s033s034lbl.pdf', 'application_number': 19297, 'submission_type': 'SUPPL ', 'submission_number': 34}
11,472	NOVANTRONE mitoXANTRONE for injection concentrate WARNING NOVANTRONE (mitoxantrone for injection concentrate) should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. NOVANTRONE should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. (See ADVERSE REACTIONS, General, Cutaneous and DOSAGE AND ADMINISTRATION, Preparation and Administration Precautions). NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result from intrathecal administration. (See WARNINGS, General) Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving NOVANTRONE . Cardiotoxicity: Congestive heart failure (CHF), potentially fatal, may occur either during therapy with NOVANTRONE or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative NOVANTRONE dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with NOVANTRONE, prescribers should consider the following: All Patients: - All patients should be assessed for cardiac signs and symptoms by history, physical examination, and ECG prior to start of NOVANTRONE therapy. - All patients should have baseline quantitative evaluation of left ventricular ejection fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated radionuclide angiography (MUGA), MRI, etc.). Multiple Sclerosis Patients: - MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE . - MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. - MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of NOVANTRONE should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during NOVANTRONE therapy. - MS patients should not receive a cumulative NOVANTRONE dose greater than 140 mg/m2. - MS patients should undergo yearly quantitative LVEF evaluation after stopping NOVANTRONE to monitor for late occurring cardiotoxicity. Secondary Leukemia: NOVANTRONE® therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda s tructural formula For additional information, see WARNINGS and DOSAGE AND ADMINISTRATION. DESCRIPTION NOVANTRONE (mitoxantrone hydrochloride) is a synthetic antineoplastic anthracenedione for intravenous use. The molecular formula is C22H28N4O62HCl and the molecular weight is 517.41. It is supplied as a concentrate that MUST BE DILUTED PRIOR TO INJECTION. The concentrate is a sterile, nonpyrogenic, dark blue aqueous solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains 0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10 anthracenedione dihydrochloride and the structural formula is: CLINICAL PHARMACOLOGY Mechanism of Action Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity. NOVANTRONE has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2. Pharmacokinetics Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of NOVANTRONE can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m2. Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low. In patients administered 15-90 mg/m2 of NOVANTRONE intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC). Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26 455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin. Metabolism and Elimination Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda their glucuronide conjugates. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. Special Populations Gender The effect of gender on mitoxantrone pharmacokinetics is unknown. Geriatric In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3 L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 for non-elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively. Pediatric Mitoxantrone pharmacokinetics in the pediatric population are unknown. Race The effect of race on mitoxantrone pharmacokinetics is unknown. Renal Impairment Mitoxantrone pharmacokinetics in patients with renal impairment are unknown. Hepatic Impairment Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than three times greater than that of patients with normal hepatic function receiving the same dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE. Other patients with hepatic impairment should be treated with caution and dosage adjustment may be required. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions: In vitro drug interaction studies have demonstrated that mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration range. The results of in vitro induction studies are inconclusive, but suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity. Pharmacokinetic studies of the interaction of NOVANTRONE with concomitantly administered medications in humans have not been performed. The pathways leading to the metabolism of NOVANTRONE have not been elucidated. To date, post-marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. CLINICAL TRIALS Multiple Sclerosis The safety and efficacy of NOVANTRONE in multiple sclerosis were assessed in two randomized, multicenter clinical studies. One randomized, controlled study (Study 1) was conducted in patients with secondary progressive or progressive relapsing multiple sclerosis. Patients in this study demonstrated significant neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5 point increments ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Patients in this study had experienced a mean deterioration in EDSS of about 1.6 points over the 18 months prior to enrollment. Patients were randomized to receive placebo, 5 mg/m2 NOVANTRONE, or 12 mg/m2 NOVANTRONE administered IV every 3 months for 2 years. High-dose methylprednisolone was administered to treat relapses. The intent-to-treat analysis cohort consisted of 188 patients; 149 completed the 2-year study. Patients were evaluated every 3 months, and clinical outcome was determined after 24 months. In addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were performed by evaluators blinded to study drug and clinical outcome, although the diagnosis of relapse and the decision to treat relapses with steroids were made by unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS, Ambulation Index [AI], number of relapses requiring treatment with steroids, months to first relapse needing treatment with steroids, and Standard Neurological Status [SNS]) was used to determine primary efficacy. The AI is an ordinal scale ranging from 0 to 9 in one point increments to define progressive ambulatory impairment. The SNS provides an overall measure of neurologic impairment and disability, with scores ranging from 0 (normal neurologic examination) to 99 (worst possible score). Results of Study 1 are summarized in Table 1. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Primary clinical variables analyzed: No. of patients with new Gd enhancing lesions Table 1 Efficacy Results at Month 24 Study 1 Treatment Groups p-value NOVANTRONE Placebo vs Primary Endpoints Placebo (N = 64) 5 mg/m2 (N = 64) 12 mg/m2 (N = 60) 12 mg/m2 NOVANTRONE Primary efficacy multivariate analysis* - - - < 0.0001 EDSS change (mean) Ambulation Index change (mean) Mean number of relapses per patient requiring corticosteroid treatment (adjusted for discontinuation) Months to first relapse requiring corticosteroid treatment (median [1st quartile]) Standard Neurological Status change (mean) 0.23 0.77 1.20 14.2 [6.7] 0.77 – 0.23 0.41 0.73 NR [6.9] – 0.38 – 0.13 0.30 0.40 NR [20.4] – 1.07 0.0194 0.0306 0.0002 0.0004 0.0269 MRI‡ - 5/32 (16%) 4/37 (11%) 0/31 0.022 Change in number of T2-weighted lesions, mean (n) 1.94 (32) 0.68 (34) 0.29 (28) 0.027 NR = not reached within 24 months; MRI = magnetic resonance imaging. * Wei-Lachin test. ** Month 24 value minus baseline. ‡ A subset of 110 patients was selected for MRI analysis. MRI results were not available for all patients at all time points. A second randomized, controlled study (Study 2) evaluated NOVANTRONE in combination with methylprednisolone (MP) and was conducted in patients with secondary progressive or worsening relapsing-remitting multiple sclerosis who had residual neurological deficit between relapses. All patients had experienced at least two relapses with sequelae or neurological deterioration within the previous 12 months. The average deterioration in EDSS was 2.2 points during the previous 12 months. During the screening period, patients were treated with two monthly doses of 1 g of IV MP and underwent monthly MRI scans. Only patients who developed at least one new Gd enhancing MRI lesion during the 2-month screening period were eligible for randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV MP alone (n = 21) or ~12 mg/m2 of IV NOVANTRONE plus 1 g of IV MP (n = 21) Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Secondary Endpoints (NOV + MP) for 6 months. Patients were evaluated monthly, and study outcome was determined after 6 months. The primary measure of effectiveness in this study was a comparison of the proportion of patients in each treatment group who developed no new Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel. Additional outcomes were measured, including EDSS and number of relapses, but all clinical measures in this trial were assessed by an unblinded treating physician. Five patients, all in the MP alone arm, failed to complete the study due to lack of efficacy. The results of this trial are displayed in Table 2. Table 2 Efficacy Results Study 2 MP alone NOV + MP Primary Endpoint (N = 21) (N = 21) p-value Patients (%) without new Gd-enhancing lesions on 5 (31%) 19 (90%) 0.001 MRIs (primary endpoint)* EDSS change (Month 6 minus baseline)* (mean) -0.1 -1.1 0.013 Annualized relapse rate (mean per patient) 3.0 0.7 0.003 Patients (%) without relapses 7 (33%) 14 (67%) 0.031 MP = methylprednisolone; NOV + MP = NOVANTRONE plus methylprednisolone. * Results at Month 6, not including data for 5 withdrawals in the MP alone group. Advanced Hormone-Refractory Prostate Cancer A multicenter Phase 2 trial of NOVANTRONE and low-dose prednisone (N + P) was conducted in 27 symptomatic patients with hormone-refractory prostate cancer. Using NPCP (National Prostate Cancer Project) criteria for disease response, there was one partial responder and 12 patients with stable disease. However, nine patients or 33% achieved a palliative response defined on the basis of reduction in analgesic use or pain intensity. These findings led to the initiation of a randomized multicenter trial (CCI-NOV22) comparing the effectiveness of (N + P) to low-dose prednisone alone (P). Eligible patients were required to have metastatic or locally advanced disease that had progressed on standard hormonal therapy, a castrate serum testosterone level, and at least mild pain Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda at study entry. NOVANTRONE was administered at a dose of 12 mg/m2 by short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg twice a day. Patients randomized to the prednisone arm were crossed over to the N + P arm if they progressed or if they were not improved after a minimum of 6 weeks of therapy with prednisone alone. A total of 161 patients were randomized, 80 to the N + P arm and 81 to the P arm. The median NOVANTRONE dose administered was 12 mg/m2 per cycle. The median cumulative NOVANTRONE dose administered was 73 mg/m2 (range of 12 to 212 mg/m2). A primary palliative response (defined as a 2-point decrease in pain intensity in a 6-point pain scale, associated with stable analgesic use, and lasting a minimum of 6 weeks) was achieved in 29% of patients randomized to N + P compared to 12% of patients randomized to P alone (p = 0.011). Two responders left the study after meeting primary response criterion for two consecutive cycles. For the purposes of this analysis, these two patients were assigned a response duration of zero days. A secondary palliative response was defined as a 50% or greater decrease in analgesic use, associated with stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response (defined as primary plus secondary responses) was achieved in 38% of patients randomized to N + P compared to 21% of patients randomized to P (p = 0.025). The median duration of primary palliative response for patients randomized to N + P was 7.6 months compared to 2.1 months for patients randomized to P alone (p = 0.0009). The median duration of overall palliative response for patients randomized to N + P was 5.6 months compared to 1.9 months for patients randomized to P alone (p = 0.0004). Time to progression was defined as a 1-point increase in pain intensity, or a > 25% increase in analgesic use, or evidence of disease progression on radiographic studies, or requirement for radiotherapy. The median time to progression for all patients randomized to N + P was 4.4 months compared to 2.3 months for all patients randomized to P alone (p = 0.0001). Median time to death was 11.3 months for all patients on the N + P arm compared to 10.8 months for all patients on P alone (p = 0.2324). Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Forty-eight patients on the P arm crossed over to receive N + P. Of these, thirty patients had progressed on P, while 18 had stable disease on P. The median cycle of crossover was 5 cycles (range of 2 to 16 cycles). Time trends for pain intensity prior to crossover were significantly worse for patients who crossed over than for those who remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response on N + P after crossover. The median time to death for patients who crossed over to N + P was 12.7 months. The clinical significance of a fall in prostate-specific antigen (PSA) concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two consecutive follow-up assessments after baseline was reported in 33% of all patients randomized to the N + P arm and 9% of all patients randomized to the P arm. These findings should be interpreted with caution since PSA responses were not defined prospectively. A number of patients were inevaluable for response, and there was an imbalance between treatment arms in the numbers of evaluable patients. In addition, PSA reduction did not correlate precisely with palliative response, the primary efficacy endpoint of this study. For example, among the 26 evaluable patients randomized to the N + P arm who had a  50% reduction in PSA, only 13 had a primary palliative response. Also, among 42 evaluable patients on this arm who did not have this reduction in PSA, 8 nonetheless had a primary palliative response. Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3 comparative trial of NOVANTRONE plus hydrocortisone (N + H) versus hydrocortisone alone (H) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible patients were required to have metastatic disease that had progressed despite at least one hormonal therapy. Progression at study entry was defined on the basis of progressive symptoms, increases in measurable or osseous disease, or rising PSA levels. NOVANTRONE was administered intravenously at a dose of 14 mg/m2 every 21 days and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242 subjects were randomized, 119 to the N + H arm and 123 to the H arm. There were no differences in survival between the two arms, with a median of 11.1 months in the N + H arm and 12 months in the H arm (p = 0.3298). Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Using NPCP criteria for response, partial responses were achieved in 10 patients (8.4%) randomized to the N + H arm compared with 2 patients (1.6%) randomized to the H arm (p = 0.018). The median time to progression, defined by NPCP criteria, for patients randomized to the N + H arm was 7.3 months compared to 4.1 months for patients randomized to H alone (p = 0.0654). Approximately 60% of patients on each arm required analgesics at baseline. Analgesic use was measured in this study using a 5-point scale. The best percent change from baseline in mean analgesic use was -17% for 61 patients with available data on the N + H arm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend analysis for analgesic use in individual patients also showed a trend favoring the N + H arm over H alone but was not statistically significant. Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2 (a 5 point scale). The best percent change from baseline in mean pain intensity was -14% for 37 patients with available data on the N + H arm, compared with +8% for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed no difference between treatment arms. Acute Nonlymphocytic Leukemia In two large randomized multicenter trials, remission induction therapy for acute nonlymphocytic leukemia (ANLL) with NOVANTRONE 12 mg/m2 daily for 3 days as a 10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a continuous 24-hour infusion was compared with daunorubicin 45 mg/m2 daily by intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with NOVANTRONE. Patients who had an incomplete antileukemic response received a second induction course in which NOVANTRONE or daunorubicin was administered for 2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates and median survival information for both the U.S. and international multicenter trials are given in Table 3: Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3 Response Rates, Time to Response, and Survival in U.S. and International Trials % Complete Median Time Trial Response (CR) to CR (days) Survival (days) NOV DAUN NOV DAUN NOV DAUN U.S. 63 (62/98) 53 (54/102) 35 42 312 237 International 50 (56/112) 51 (62/123) 36 42 192 230 NOV = NOVANTRONE + cytarabine DAUN = daunorubicin + cytarabine In these studies, two consolidation courses were administered to complete responders on each arm. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but only 5 days of cytarabine and 2 days of NOVANTRONE or daunorubicin were given. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission. The second consolidation course was generally administered 4 weeks later. Full hematologic recovery was necessary for patients to receive consolidation therapy. For the U.S. trial, median granulocyte nadirs for patients receiving NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 10/mm3 for both courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively. Median platelet nadirs for patients who received NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients who achieve a complete remission remains controversial. However, in the only well- controlled prospective, randomized multicenter trials with NOVANTRONE in ANLL, consolidation therapy was given to all patients who achieved a complete remission. During consolidation in the U.S. study, two myelosuppression-related deaths occurred on the NOVANTRONE arm and one on the daunorubicin arm. However, in the international study there were eight deaths on the NOVANTRONE arm during consolidation which were related to the myelosuppression and none on the daunorubicin arm where less myelosuppression occurred. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE NOVANTRONE is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). NOVANTRONE is not indicated in the treatment of patients with primary progressive multiple sclerosis. The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability. NOVANTRONE in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer. NOVANTRONE in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. CONTRAINDICATIONS NOVANTRONE is contraindicated in patients who have demonstrated prior hypersensitivity to it. WARNINGS WHEN NOVANTRONE IS USED IN HIGH DOSES (> 14 mg/m2/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT NOVANTRONE BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. NOVANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION. General Patients with preexisting myelosuppression as the result of prior drug therapy should not receive NOVANTRONE unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression. The safety of NOVANTRONE (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY). Safety for use by routes other than intravenous administration has not been established. NOVANTRONE is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. NOVANTRONE must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction. Topoisomerase II inhibitors, including NOVANTRONE, have been associated with the development of secondary acute myeloid leukemia and myelosuppression. Cardiac Effects Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE therapy in such patients should be determined before starting therapy. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with NOVANTRONE. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%. Multiple Sclerosis Changes in cardiac function may occur in patients with multiple sclerosis treated with NOVANTRONE. In one controlled trial (Study 1, see CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving NOVANTRONE, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2 dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial. MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of NOVANTRONE therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with NOVANTRONE. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. NOVANTRONE should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda LVEF evaluation after stopping NOVANTRONE to monitor for late-occurring cardiotoxicity. Leukemia Acute congestive heart failure may occasionally occur in patients treated with NOVANTRONE for ANLL. In first-line comparative trials of NOVANTRONE + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease. Hormone-Refractory Prostate Cancer Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with NOVANTRONE. In a randomized comparative trial of NOVANTRONE plus low-dose prednisone vs low- dose prednisone, 7 of 128 patients (5.5 %) treated with NOVANTRONE had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total NOVANTRONE dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m2. Among 112 patients evaluable for safety on the NOVANTRONE + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total NOVANTRONE doses administered to these patients is not available. Pregnancy NOVANTRONE may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m2 basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus. Secondary Leukemia NOVANTRONE® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis. In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup. In a prospective, open-label, tolerability and safety monitoring study of NOVANTRONE® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with NOVANTRONE® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia. In 1774 patients with breast cancer who received NOVANTRONE concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment- related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with NOVANTRONE, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years. Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. NOVANTRONE is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections. PRECAUTIONS General Therapy with NOVANTRONE should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation. Systemic infections should be treated concomitantly with or just prior to commencing therapy with NOVANTRONE. Information for Patients See FDA-approved patient labeling (Medication Guide). Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Novantrone and prior to each infusion. Review the Novantrone Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Novantrone should be taken only as prescribed. Advise patients that Novantrone can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that Novantrone can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda failure. Advise patients receiving Novantrone to treat multiple sclerosis that they should receive cardiac monitoring prior to each Novantrone dose and yearly after stopping Novantrone. NOVANTRONE may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur. Laboratory Tests A complete blood count, including platelets, should be obtained prior to each course of NOVANTRONE and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by NOVANTRONE. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy. Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Intravenous treatment of rats and mice, once every 21 days for 24 months, with NOVANTRONE resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m2 basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m2 basis). Intravenous treatment of rats, once every 21 days for 12 months with NOVANTRONE resulted in an increased Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m2 basis). Mutagenesis NOVANTRONE was clastogenic in the in vivo rat bone marrow assay. NOVANTRONE was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. NOVANTRONE was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma). Drug Interactions Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation. To date, post- marketing experience has not revealed any significant drug interactions in patients who have received NOVANTRONE for treatment of cancer. Information on drug interactions in patients with multiple sclerosis is limited. Following concurrent administration of NOVANTRONE with corticosteroids, no evidence of drug interactions has been observed. Special Populations Hepatic Impairment Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with NOVANTRONE. NOVANTRONE should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function. Pregnancy Pregnancy Category D (see WARNINGS). Nursing Mothers Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOVANTRONE is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from NOVANTRONE, breast feeding should be discontinued before starting treatment. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Multiple Sclerosis: Clinical studies of Novantrone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients (<65 years) have been treated with Novantrone in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out. Acute Nonlymphocytic Leukemia: Although definitive studies with Novantrone have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy. ADVERSE REACTIONS Multiple Sclerosis NOVANTRONE has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received NOVANTRONE in combination with corticosteroids. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m2 NOVANTRONE arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the NOVANTRONE groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea. Table 4a summarizes clinical adverse events of all intensities occurring in  5% of patients in either dose group of NOVANTRONE and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m2 group). Of note, alopecia consisted of mild hair thinning. Two of the 127 patients treated with NOVANTRONE in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m2 did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4a Adverse Events of Any Intensity Occurring in  5% of Patients on Any Dose of NOVANTRONE and That Were Numerically Greater Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Preferred Term (N = 64) (N = 65) (N = 62) Nausea 20 55 76 Alopecia 31 38 61 Menstrual disorder * 26 51 61 Amenorrhea * 3 28 43 Upper respiratory tract infection 52 51 53 Urinary tract infection 13 29 32 Stomatitis 8 15 19 Arrhythmia 8 6 18 Diarrhea 11 25 16 Urine abnormal 6 5 11 ECG abnormal 3 5 11 Constipation 6 14 10 Back pain 5 6 8 Sinusitis 2 3 6 Headache 5 6 6 * Percentage of female patients. The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m2 group, and 81% for the 12 mg/m2 group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m2 patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m2 patients (tonsillitis, urinary tract infection [two], endometritis). Table 4b summarizes laboratory abnormalities that occurred in  5% of patients in either NOVANTRONE dose group, and that were numerically more frequent than in the placebo group. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4b Laboratory Abnormalities Occurring in  5% of Patients* on Either Dose of NOVANTRONE and That Were More Frequent Than in the Placebo Group Study 1 Percent of Patients 5 mg/m2 12 mg/m2 Placebo NOVANTRONE NOVANTRONE Event (N = 64) (N = 65) (N = 62) Leukopenia a 0 9 19 Gamma-GT increased 3 3 15 SGOT increased 8 9 8 Granulocytopenia b 2 6 6 Anemia 2 9 6 SGPT increased 3 6 5 * Assessed using World Health Organization (WHO) toxicity criteria. a. < 4000 cells/mm3 b. < 2000 cells/mm3 There was no difference among treatment groups in the incidence or severity of hemorrhagic events. In Study 2, NOVANTRONE was administered once a month. Clinical adverse events most frequently reported in the NOVANTRONE group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the NOVANTRONE group and numerically more frequent than in the control group. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 5a Adverse Events of Any Intensity Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) Amenorrhea a 0 53 Alopecia 0 33 Nausea 0 29 Asthenia 0 24 Pharyngitis/throat infection 5 19 Gastralgia/stomach burn/epigastric pain 5 14 Aphthosis 0 10 Cutaneous mycosis 0 10 Rhinitis 0 10 Menorrhagia a 0 7 N = NOVANTRONE, MP = methylprednisolone * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. Percentage of female patients. Table 5b Laboratory Abnormalities Occurring in > 5% of Patients* in the NOVANTRONE Group and Numerically More Frequent Than in the Control Group Study 2 Percent of Patients MP N + MP Event (n = 21) (n = 21) WBC low a 14 100 ANC low b 10 100 Lymphocytes low 43 95 Hemoglobin low 48 43 Platelets low c 0 33 SGOT high 5 15 SGPT high 10 15 Glucose high 5 10 Potassium low 0 10 N = NOVANTRONE, MP = methylprednisolone. * Assessed using National Cancer Institute (NCI) common toxicity criteria. a. < 4000 cells/mm3 b. < 1500 cells/mm3 c. < 100,000 cells/mm3 Leukopenia and neutropenia were reported in the N +MP group (see Table 5b). Neutropenia occurred within 3 weeks after NOVANTRONE administration and was Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons. Leukemia NOVANTRONE has been studied in approximately 600 patients with acute non lymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of NOVANTRONE + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression. Table 6 summarizes adverse reactions occurring in patients treated with NOVANTRONE + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial. Adverse reactions are presented as major categories and selected examples of clinically significant subcategories. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 6 Adverse Events Occurring in ANLL Patients Receiving NOVANTRONE or Daunorubicin Induction Consolidation [% pts entering induction] NOV DAUN [% pts entering induction] NOV DAUN Event N = 102 N = 102 N = 55 N = 49 Cardiovascular 26 28 11 24 CHF 5 6 0 0 Arrhythmias 3 3 4 4 Bleeding 37 41 20 6 GI 16 12 2 2 Petechiae/ecchymoses 7 9 11 2 Gastrointestinal 88 85 58 51 Nausea/vomiting 72 67 31 31 Diarrhea 47 47 18 8 Abdominal pain 15 9 9 4 Mucositis/stomatitis 29 33 18 8 Hepatic 10 11 14 2 Jaundice 3 8 7 0 Infections 66 73 60 43 UTI 7 2 7 2 Pneumonia 9 7 9 0 Sepsis 34 36 31 18 Fungal infections 15 13 9 6 Renal failure 8 6 0 2 Fever 78 71 24 18 Alopecia 37 40 22 16 Pulmonary 43 43 24 14 Cough 13 9 9 2 Dyspnea 18 20 6 0 CNS 30 30 34 35 Seizures 4 4 2 8 Headache 10 9 13 8 Eye 7 6 2 4 Conjunctivitis 5 1 0 0 NOV = NOVANTRONE, DAUN = daunorubicin. Hormone-Refractory Prostate Cancer Detailed safety information is available for a total of 353 patients with hormone- refractory prostate cancer treated with NOVANTRONE, including 274 patients who received NOVANTRONE in combination with corticosteroids. Table 7 summarizes adverse reactions of all grades occurring in  5% of patients in Trial CCI-NOV22. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 7 Adverse Events of Any Intensity Occurring in  5% of Patients Trial CCI-NOV22 N + P P (n = 80) (n = 81) Event % % Nausea 61 35 Fatigue 39 14 Alopecia 29 0 Anorexia 25 6 Constipation 16 14 Dyspnea 11 5 Nail bed changes 11 0 Edema 10 4 Systemic infection 10 7 Mucositis 10 0 UTI 9 4 Emesis 9 5 Pain 8 9 Fever 6 3 Hemorrhage/bruise 6 1 Anemia 5 3 Cough 5 0 Decreased LVEF 5 0 Anxiety/depression 5 3 Dyspepsia 5 6 Skin infection 5 3 Blurred vision 3 5 N = NOVANTRONE, P = prednisone. No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients. Table 8 summarizes adverse events of all grades occurring in  5% of patients in Trial CALGB 9182. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 8 Adverse Events of Any Intensity Occurring in  5 % of Patients Trial CALGB 9182 N + H H (n = 112) (n = 113) Event n % n % Decreased WBC 96 87 4 4 Abnormal granulocytes/bands 88 79 3 3 Decreased hemoglobin 83 75 42 39 Abnormal lymphocytes count 78 72 27 25 Pain 45 41 44 39 Abnormal platelet count 43 39 8 7 Abnormal alkaline phosphatase 41 37 42 38 Malaise/fatigue 37 34 16 14 Hyperglycemia 33 31 32 30 Edema 31 30 15 14 Nausea 28 26 9 8 Anorexia 24 22 16 14 Abnormal BUN 24 22 22 20 Abnormal Transaminase 22 20 16 14 Alopecia 20 20 1 1 Abnormal Cardiac function 19 18 0 0 Infection 18 17 4 4 Weight loss 18 17 13 12 Dyspnea 16 15 9 8 Diarrhea 16 14 4 4 Fever in absence of infection 15 14 7 6 Weight gain 15 14 16 15 Abnormal creatinine 14 13 11 10 Other gastrointestinal 13 14 11 11 Vomiting 12 11 6 5 Other neurologic 11 11 5 5 Hypocalcemia 10 10 5 5 Hematuria 9 11 5 6 Hyponatremia 9 9 3 3 Sweats 9 9 2 2 Other liver 8 8 8 8 Stomatitis 8 8 1 1 Cardiac dysrhythmia 7 7 3 3 Hypokalemia 7 7 4 4 Neuro/constipation 7 7 2 2 Neuro/motor disorder 7 7 3 3 Neuro/mood disorder 6 6 2 2 Skin disorder 6 6 4 4 Cardiac ischemia 5 5 1 1 Chills 5 5 0 0 Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hemorrhage 5 5 3 3 Myalgias/arthralgias 5 5 3 3 Other kidney/bladder 5 5 3 3 Other endocrine 5 6 3 4 Other pulmonary 5 5 3 3 Hypertension 4 4 5 5 Impotence/libido 4 7 2 3 Proteinuria 4 6 2 3 Sterility 3 5 2 3 N= NOVANTRONE, H= hydrocortisone General Allergic Reaction Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely. Cutaneous Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion. Hematologic Topoisomerase II inhibitors, including NOVANTRONE, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see WARNINGS). Leukemia Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens. Hormone-Refractory Prostate Cancer In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm3, Grade 4 neutropenia (ANC < 500 /mm3) was observed in 54% of patients treated with NOVANTRONE + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m2, Grade 4 neutropenia in 23% of patients Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda treated with NOVANTRONE + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving NOVANTRONE + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm3 were noted in 4% and 3% of patients receiving NOVANTRONE + corticosteroids on these trials, and there was one patient death on NOVANTRONE + hydrocortisone due to intracranial hemorrhage after a fall. Gastrointestinal Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy. Cardiovascular Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS) Pulmonary Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included NOVANTRONE. OVERDOSAGE There is no known specific antidote for NOVANTRONE. Accidental overdoses have been reported. Four patients receiving 140-180 mg/m2 as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression. Although patients with severe renal failure have not been studied, NOVANTRONE is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE AND ADMINISTRATION (See also WARNINGS) Multiple Sclerosis The recommended dosage of NOVANTRONE is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of NOVANTRONE and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with NOVANTRONE NOVANTRONE should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of > 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of NOVANTRONE and in the event that signs or symptoms of infection develop. NOVANTRONE generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. NOVANTRONE therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because NOVANTRONE clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments. Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of NOVANTRONE (see WARNINGS, Pregnancy). Hormone-Refractory Prostate Cancer Based on data from two Phase 3 comparative trials of NOVANTRONE plus corticosteroids versus corticosteroids alone, the recommended dosage of NOVANTRONE is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Combination Initial Therapy for ANLL in Adults For induction, the recommended dosage is 12 mg/m2 of NOVANTRONE daily on Days 1-3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7. Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. NOVANTRONE should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves. Consolidation therapy which was used in two large randomized multicenter trials consisted of NOVANTRONE, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1-5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY) Hepatic Impairment For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment) Preparation and Administration Precautions NOVANTRONE CONCENTRATE MUST BE DILUTED PRIOR TO USE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The dose of NOVANTRONE should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). NOVANTRONE Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE. NOVANTRONE should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that NOVANTRONE not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted NOVANTRONE concentrate should be stored not longer than 7 days between 15-25C (59-77F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE. Care in the administration of NOVANTRONE will reduce the chance of extravasation. NOVANTRONE should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of NOVANTRONE with the skin, mucous membranes, or eyes. NOVANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of NOVANTRONE extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction. Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin accidentally exposed to NOVANTRONE should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm_vi_2.html. 3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) Pittsburgh, PA: Oncology Nursing Society. HOW SUPPLIED NOVANTRONE (mitoxantrone for injection concentrate) is a sterile aqueous solution containing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multidose use as follows: NDC 44087-1520-1 - 20 mg/10 mL/multidose vial (2 mg/mL) NOVANTRONE (mitoxantrone for injection concentrate) should be stored between 15-25C (59-77F). DO NOT FREEZE. Issue Date: March/2012 Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Manufactured for: EMD Serono, Inc. Rockland, MA 02370 USA Reference ID: 3105100 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:20.786028	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019297s035lbl.pdf', 'application_number': 19297, 'submission_type': 'SUPPL ', 'submission_number': 35}
11,477	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:21.094898	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019322s018lbl.pdf', 'application_number': 19323, 'submission_type': 'SUPPL ', 'submission_number': 19}
11,476	This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:21.429660	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019322s018lbl.pdf', 'application_number': 19322, 'submission_type': 'SUPPL ', 'submission_number': 18}
11,478	Heparin Sodium in 5% Dextrose Injection Rx only 12,500 USP Heparin Units/250 mL (50 USP Heparin Units/mL) 10,000 USP Heparin Units/100 mL (100 USP Heparin Units/mL) or 25,000 USP Heparin Units/250 mL (100 USP Heparin Units/mL) company logo Flexible Plastic Container Do not admix with other drugs. DESCRIPTION Intravenous solutions with heparin sodium (derived from porcine intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration. Each 100 mL contains heparin sodium 4,000, 5,000 or 10,000 USP Heparin Units; dextrose, hydrous 5 g; citric acid, anhydrous, 51 mg and sodium citrate, dihydrate 334 mg added as buffers; sodium metabisulfite 20 mg added as an antioxidant. Each liter contains electrolytes sodium and citrate in amounts as listed in HOW SUPPLIED Table. See Table for summary of contents and characteristics of this solution. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)>(1)>(4)>(3)>(5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. Structure of Heparin Sodium (representative subunits): structural formula Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose sugar freely soluble in water. It has the following structural formula: structural formula Water for Injection, USP is chemically designated H2O. wEN-3454v02 Page 1 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The flexible plastic container is fabricated from a specially formulated nonplasticized, thermoplastic co-polyester (CR3). Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of its chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. CLINICAL PHARMACOLOGY Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases it is not measurably affected by low doses of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time for a wide range of dose levels are linear which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. INDICATIONS AND USAGE Heparin sodium is indicated for: Atrial fibrillation with embolization; Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation); Prevention of clotting in arterial and heart surgery; Prophylaxis and treatment of peripheral arterial embolism; As an anticoagulant in extracorporeal arterial circulation and dialysis procedures. CONTRAINDICATIONS Heparin sodium should not be used in patients: With severe thrombocytopenia; With a known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) (See ADVERSE REACTIONS, hypersensitivity); In whom suitable blood coagulation tests – e.g., the whole blood clotting time, partial thromboplastin time, etc. – cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin); With an uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation. wEN-3454v02 Page 2 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products. WARNINGS Heparin is not intended for intramuscular use. Hypersensitivity: Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations. (See ADVERSE REACTIONS, Hypersensitivity.) Because Heparin Sodium in 5% Dextrose Injection is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy. Hemorrhage: Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure, or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are: Cardiovascular – Subacute bacterial endocarditis. Severe hypertension. Surgical – During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye. Hematologic – Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras. Gastrointestinal – Ulcerative lesions and continuous tube drainage of the stomach or small intestine. Other – Menstruation, liver disease with impaired hemostasis. Coagulation Testing: When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin should be discontinued promptly (See OVERDOSAGE). Thrombocytopenia: Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (See Heparin-induced Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered. Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis): HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes. Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of wEN-3454v02 Page 3 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin sodium, or platelet activation induced by heparin sodium. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin sodium in heparin sodium-naïve individuals, and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin sodium initiation), especially in patients with a recent exposure to heparin sodium (i.e. previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation. Delayed Onset of HIT (With or Without Thrombosis): Heparin-induced Thrombocytopenia (with or without thrombosis) can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT (with or without thrombosis). Other: This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration. Solutions containing dextrose without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration. Excessive administration of potassium-free solutions may result in significant hypokalemia. Because dosages of this drug are titrated to response (See DOSAGE AND ADMINISTRATION), no additives should be made to Heparin Sodium in 5% Dextrose Injection. PRECAUTIONS General a. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis): (See WARNINGS). b. Heparin Resistance: Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. c. Increased Risk to Older Patients, Especially Women: A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance and electrolyte concentrations during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. wEN-3454v02 Page 4 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Solutions containing dextrose should be used with caution in patients with overt or known subclinical diabetes mellitus, or carbohydrate intolerance for any reason. Do not use plastic container in series connection. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. These solutions are intended for intravenous administration using sterile equipment. It is recommended that any unused heparin solution and intravenous administration apparatus be replaced at least once every 24 hours. Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, (See DOSAGE AND ADMINISTRATION). Drug Interactions Oral Anticoagulants: Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. Platelet Inhibitors: Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other Interactions: Digitalis, tetracyclines, nicotine, antihistamines, or IV nitroglycerine may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Drug/Laboratory Tests Interactions Hyperaminotransferasemia: Significant elevations of aminotransferase AST (SGOT) and ALT (SGPT) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, rises that might be caused by drugs (like heparin) should be interpreted with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to determine effects on fertility of males and females, and the studies to determine mutagenic potential have not been conducted with Heparin Sodium in 5% Dextrose Injection. Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin sodium does not cross the placenta, based on human and animal studies. Administration of heparin to pregnant animals at doses higher than the maximum human wEN-3454v02 Page 5 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight. The number of early resorptions increased in both species. There was no evidence of teratogenic effects. Nursing Mothers Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. Exercise caution when administering Heparin Sodium to a nursing mother. Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience (See DOSAGE AND ADMINISTRATION, Pediatric Use). Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (See PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS Hemorrhage: Hemorrhage is the chief complication that may result from heparin therapy (See WARNINGS). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (See OVERDOSAGE). It should be appreciated that gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: a. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient’s death. b. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication if unrecognized may be fatal. c. Retroperitoneal hemorrhage. Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis): (See WARNINGS.) Local Irritation: Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended. Hypersensitivity: Generalized hypersensitivity reactions have been reported, with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid wEN-3454v02 Page 6 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur. (See WARNINGS.) Certain episodes of painful, ischemic, and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia associated complications remains to be determined. Miscellaneous: Osteoporosis following long-term administration of high-doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. Significant elevations of aminotransferase AST (SGOT) and ALT (SGPT) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. OVERDOSAGE Symptoms: Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding. Treatment: Neutralization of heparin effect. When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin Units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about ½ hour after intravenous injection. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information the labeling of Protamine Sulfate Injection, USP products should be consulted. DOSAGE AND ADMINISTRATION Heparin sodium is not effective by oral administration and these premixed formulations should be given by intermittent intravenous injection or intravenous infusion. The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. wEN-3454v02 Page 7 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Converting to Oral Anticoagulant When an oral anticoagulant of the coumarin or similar type is to be started in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about 5 hours after the last IV bolus. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time. In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering. Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines: Method of Administration Frequency Recommended Dose* Intermittent Intravenous Injection Initial Dose 10,000 Units, either undiluted or in 50 – 100 mL of 5% Dextrose Injection Every 4 to 6 hours 5,000 – 10,000 Units, either undiluted or in 50 – 100 mL of 5% Dextrose Injection Continuous Intravenous Infusion Initial Dose 5,000 Units by IV injection Continuous 20,000 – 40,000 Units/24 hours in 1000 mL of 5% Dextrose Injection *Based on 150 lb. (68 kg) patient. Pediatric Use There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients: Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes) Maintenance Dose Infants: 25 to 30 units/kg/hour; Infants <2 months have the highest requirements (average 28 units/kg/hour) Children >1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage Monitoring Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70. Geriatric Use Patients over 60 years of age may require lower doses of heparin (see PRECAUTIONS). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and container is undamaged. Discard unused portion. INSTRUCTIONS FOR USE To Open Tear outer wrap at notch and remove solution container. wEN-3454v02 Page 8 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: When using a vented administration set, replace bacterial retentive air filter with piercing pin cover. Insert piercing pin with twisting motion until shoulder of air filter housing rests against the outlet port flange. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Open clamp to expel air from set. Close clamp. 7. Perform venipuncture and attach set to venipuncture device. 8. Regulate rate of administration with flow control clamp. WARNING: Do not use flexible container in series connections. HOW SUPPLIED Heparin Sodium in 5% Dextrose is supplied in single-dose flexible plastic containers in various sizes and concentrations as shown in the accompanying Table. Contents and Characteristics Per 100 mL NDC No. Product Heparin Sodium (USP Heparin Units/mL) Heparin Sodium (USP Heparin Units) Dextrose (hydrous) Sodium mEq/L Citrate mEq/L Tonicity Osmolarity mOsmol/ liter (calc.) pH Solution Volume 0409-7793-62 Heparin Sodium 25,000 USP Heparin Units/250 mL (100 USP Heparin Units/mL) in 5% Dextrose Injection 100 10,000 5 g 39 42 Isotonic 304 5.7 (5.0 to 6.0) 250 mL 0409-7793-23 Heparin Sodium 10,000 USP Heparin Units/100 mL (100 USP Heparin Units/mL) in 5% Dextrose Injection 100 10,000 5 g 39 42 Isotonic 304 5.7 (5.0 to 6.0) 100 mL 0409-7794-62 Heparin Sodium 12,500 USP Heparin Units/250 mL (50 USP Heparin Units/mL) in 5% Dextrose Injection 50 5,000 5 g 38 42 Isotonic 304 5.7 (5.0 to 6.0) 250 mL Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Revised: 2/2014 wEN-3454v02 Page 9 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda EN-3454 Hospira, Inc., Lake Forest, IL 60045 USA company logo wEN-3454v02 Page 10 of 10 Reference ID: 3470278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:21.481907	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019339s054lbl.pdf', 'application_number': 19339, 'submission_type': 'SUPPL ', 'submission_number': 54}
11,479	Alfentanil HCl Injection, USP CII Rx only DESCRIPTION Alfentanil HCl Injection, USP is an opioid analgesic chemically designated as N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo 1H-tetrazol-1- yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride (1:1) with a molecular weight of 452.98 and an n-octanol:water partition coefficient of 128:1 at pH 7.4. The structural formula of Alfentanil hydrochloride is: structural formula C21H32N6O3•HCl•H2O Formula Wt. 471.0 Alfentanil HCl Injection, USP is a sterile, non-pyrogenic, preservative free aqueous solution containing alfentanil hydrochloride equivalent to 500 mcg per mL of alfentanil base for intravenous injection. The solution, which contains sodium chloride for isotonicity, has a pH range of 4.0 to 6.0. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and Water for Injection q.s. CLINICAL PHARMACOLOGY Alfentanil is an opioid analgesic with a rapid onset of action. At doses of 8 to 40 mcg/kg for surgical procedures lasting up to 30 minutes, alfentanil provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages. For longer procedures, doses of up to 75 mcg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50 to75 mcg/kg followed by a continuous infusion of 0.5 to 3 mcg/kg/min, alfentanil attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 mcg/kg, alfentanil provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated patients may require lower doses. High intrasubject and intersubject variability in the pharmacokinetic disposition of alfentanil has been reported. The pharmacokinetics of alfentanil can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90 to 111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 mcg). The liver is the major site of biotransformation. Alfentanil has an apparent volume of distribution of 0.4 to 1 L/kg, which is approximately one-fourth to one-tenth that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared to approximately 8 mL/kg/min for fentanyl. Only 1% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of alfentanil is approximately 92%. In one study involving 15 patients administered alfentanil with nitrous oxide/oxygen, a narrow range of plasma alfentanil concentrations, approximately 310 to 340 ng/mL, was shown to provide adequate anesthesia for intra abdominal surgery, while lower concentrations, approximately 190 ng/mL, blocked responses to skin closure. Plasma concentrations between 100 to 200 ng/mL provided adequate anesthesia for superficial surgery. page 1 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Alfentanil has an immediate onset of action. At dosages of approximately 105 mcg/kg, alfentanil produces hypnosis as determined by EEG patterns; an anesthetic ED90 of 182 mcg/kg for alfentanil in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130 to 245 mcg/kg. For procedures lasting 30 to 60 minutes, loading dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal intubation and skin incision as comparable to those from fentanyl. A pre-intubation loading dose of 50 to 75 mcg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of alfentanil infusion administered at a rate of 0.5 to 3 mcg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane. Requirements for volatile inhalation anesthetics were reduced by thirty to fifty percent during the first 60 minutes of maintenance in patients administered anesthetic doses (above 130 mcg/kg) of alfentanil as compared to patients given doses of 4 to 5 mg/kg thiopental for anesthetic induction. At anesthetic induction dosages, alfentanil provides a deep level of anesthesia during the first hour of anesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision. Following an anesthetic induction dose of alfentanil, requirements for alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance. Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination for alfentanil, which may prolong postoperative recovery. Repeated or continuous administration of alfentanil produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance. Bradycardia may be seen in patients administered alfentanil. The incidence and degree of bradycardia may be more pronounced when alfentanil is administered in conjunction with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine. Administration of intravenous diazepam immediately prior to or following high doses of alfentanil has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged. Patients administered doses up to 200 mcg/kg of alfentanil have shown no significant increase in histamine levels and no clinical evidence of histamine release. Skeletal muscle rigidity is related to the dose and speed of administration of alfentanil. Muscular rigidity will occur with an immediate onset following anesthetic induction dosages. Preventative measures (see WARNINGS) may reduce the rate and severity. The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses. During monitored anesthesia care (MAC), attention must be given to the respiratory effects of alfentanil. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur. (See WARNINGS) INDICATIONS AND USAGE Alfentanil HCl injection is indicated: as an analgesic adjunct given in incremental doses in the maintenance of anesthesia with barbiturate/nitrous oxide/oxygen. as an analgesic administered by continuous infusion with nitrous oxide/oxygen in the maintenance of general anesthesia. as a primary anesthetic agent for the induction of anesthesia in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required. as the analgesic component for monitored anesthesia care (MAC). SEE DOSAGE CHART FOR MORE COMPLETE INFORMATION ON THE USE OF ALFENTANIL HCl INJECTION. CONTRAINDICATIONS Alfentanil is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists. page 2 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda WARNINGS ALFENTANIL SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS AND GENERAL ANESTHETIC AGENTS AND IN THE MANAGEMENT OF RESPIRATORY EFFECTS OF POTENT OPIOIDS. AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE. BECAUSE OF THE POSSIBILITY OF DELAYED RESPIRATORY DEPRESSION, MONITORING OF THE PATIENT MUST CONTINUE WELL AFTER SURGERY. Alfentanil administered in initial dosages up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of alfentanil at anesthetic induction dosages (above 130 mcg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of alfentanil at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of alfentanil and a full paralyzing dose of a neuromuscular blocking agent when alfentanil is used in rapidly administered anesthetic dosages (above 130 mcg/kg). The neuromuscular blocking agent used should be appropriate for the patient’s cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. PATIENTS RECEIVING MONITORED ANESTHESIA CARE (MAC) SHOULD BE CONTINUOUSLY MONITORED BY PERSONS NOT INVOLVED IN THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE; OXYGEN SUPPLEMENTATION SHOULD BE IMMEDIATELY AVAILABLE AND PROVIDED WHERE CLINICALLY INDICATED; OXYGEN SATURATION SHOULD BE CONTINUOUSLY MONITORED; THE PATIENT SHOULD BE OBSERVED FOR EARLY SIGNS OF HYPOTENSION, APNEA, UPPER AIRWAY OBSTRUCTION AND/OR OXYGEN DESATURATION. Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with alfentanil. Therefore when alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is recommended. PRECAUTIONS DELAYED RESPIRATORY DEPRESSION, RESPIRATORY ARREST, BRADYCARDIA, ASYSTOLE, ARRHYTHMIAS AND HYPOTENSION HAVE ALSO BEEN REPORTED. THEREFORE, VITAL SIGNS MUST BE MONITORED CONTINUOUSLY. General: The initial dose of alfentanil should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses. In obese patients (more than 20% above ideal total body weight), the dosage of alfentanil should be determined on the basis of lean body weight. In one clinical trial, the dose of alfentanil required to produce anesthesia, as determined by appearance of delta waves in EEG, was 40% lower in geriatric patients than that needed in healthy young patients. In patients with compromised liver function and in geriatric patients, the plasma clearance of alfentanil may be reduced and postoperative recovery may be prolonged. Induction doses of alfentanil should be administered slowly (over three minutes). Administration may produce loss of vascular tone and hypotension. Consideration should be given to fluid replacement prior to induction. Diazepam administered immediately prior to or in conjunction with high doses of alfentanil may produce vasodilation, hypotension and result in delayed recovery. Bradycardia produced by alfentanil may be treated with atropine. Severe bradycardia and asystole have been page 3 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda successfully treated with atropine and conventional resuscitative methods. The hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. Following an anesthetic induction dose of alfentanil, requirements for volatile inhalation anesthetics or alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance. Alfentanil infusions should be discontinued at least 10-15 minutes prior to the end of surgery during general anesthesia. During administration of alfentanil for Monitored Anesthesia Care (MAC), infusions may be continued to the end of the procedure. Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by alfentanil may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the postoperative period. Intraoperative hyperventilation may further alter postoperative response to CO2. Appropriate postoperative monitoring should be employed, particularly after infusions and large doses of alfentanil, to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area. Head Injuries: Alfentanil should be used with caution in patients with head injury or increased intracranial pressure, due to the increased risk of respiratory depression. As with all opioids, alfentanil may obscure the clinical course of patients with head injuries and should be used only if clinically indicated. Impaired Respiration: Alfentanil should be used with caution in patients with pulmonary disease, decreased respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration. Impaired Hepatic or Renal Function: In patients with liver or kidney dysfunction, alfentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of alfentanil. Drug Interactions: Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when alfentanil is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction. The concomitant use of erythromycin with alfentanil can significantly inhibit alfentanil clearance and may increase the risk of prolonged or delayed respiratory depression. Cimetidine reduces the clearance of alfentanil. Therefore smaller alfentanil doses will be required with prolonged administration and the duration of action of alfentanil may be extended. Perioperative administration of drugs affecting hepatic blood flow or enzyme function may reduce plasma clearance and prolong recovery. Carcinogenesis, Mutagenesis and Impairment of Fertility: No long-term animal studies of alfentanil have been performed to evaluate carcinogenic potential. No structural chromosome mutations were produced in the in vivo micronucleus test in female rats at single intravenous doses of alfentanil as high as 20 mg/kg body weight (approximately 40 times the upper human dose), equivalent to a dose of 103 mg/m2 body surface area. No dominant lethal mutations were produced in the in vivo dominant lethal test in male and female mice at the maximum intravenous dose of 20 mg/kg (60 mg/m2). No mutagenic activity was revealed in the in vitro Ames Salmonella typhimurium test, with and without metabolic activation. Pregnancy Category C: Alfentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects could have been due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug. page 4 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda No evidence of teratogenic effects has been observed after administration of alfentanil in rats or rabbits. There are no adequate and well-controlled studies in pregnant women. Alfentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: There are insufficient data to support the use of alfentanil in labor and delivery. Placental transfer of the drug has been reported; therefore, use in labor and delivery is not recommended. Nursing Mothers: In one study of nine women undergoing postpartum tubal ligation, significant levels of alfentanil were detected in colostrum four hours after administration of 60 mcg/kg of alfentanil, with no detectable levels present after 28 hours. Caution should be exercised when alfentanil is administered to a nursing woman. Pediatric Use: Adequate data to support the use of alfentanil in children under 12 years of age are not presently available. ADVERSE REACTIONS The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of respiratory depression and skeletal muscle rigidity. The adverse experience profile from 696 patients receiving alfentanil for Monitored Anesthesia Care (MAC) is similar to the profile established with alfentanil during general anesthesia. Respiratory events reported during MAC included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for MAC, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation. The following adverse reaction information is derived from controlled and open clinical trials in 785 patients who received intravenous alfentanil during induction and maintenance of general anesthesia. The controlled trials included treatment comparisons with fentanyl, thiopental sodium, enflurane, saline placebo and halothane. The incidence of certain side effects is influenced by the type of use, e.g., chest wall rigidity has a higher reported incidence in clinical trials of alfentanil induction, and by the type of surgery, e.g., nausea and vomiting have a higher reported incidence in patients undergoing gynecologic surgery. The overall reports of nausea and vomiting with alfentanil were comparable to fentanyl. Incidence Greater than 1% - Probably Causally Related (Derived from clinical trials) Gastrointestinal: nausea (28%), vomiting (18%) Cardiovascular: arrhythmia, bradycardia (14%), hypertension (18%), hypotension (10%), tachycardia (12%) Musculoskeletal: chest wall rigidity (17%), skeletal muscle movements* Respiratory: apnea, postoperative respiratory depression Central Nervous System: blurred vision, dizziness, sleepiness/postoperative sedation Incidence 3% to 9% All others 1% to 3% Incidence Less than 1% - Probably Causally Related (Derived from clinical trials) Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized. page 5 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Body as a whole: anaphylaxis Central Nervous System: headache, myoclonic movements, postoperative confusion, postoperative euphoria, shivering* Dermatological: itching, urticaria Injection Site: pain* Musculoskeletal: skeletal muscle rigidity of neck and extremities Respiratory: bronchospasm, hypercarbia, laryngospasm *Incidence 0.3% to 1% DRUG ABUSE AND DEPENDENCE Alfentanil is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused. Opioid analgesics have been associated with abuse and dependence in health care providers and others with ready access to such drugs. Alfentanil should be handled accordingly. OVERDOSAGE Overdosage would be manifested by extension of the pharmacological actions of alfentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. No experience of overdosage with alfentanil was reported during clinical trials. The intravenous LD50 of alfentanil is 43 to 51 mg/kg in rats, 72 to 74 mg/kg in mice, 72 to 82 mg/kg in guinea pigs and 60 to 88 mg/kg in dogs. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with alfentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability. DOSAGE AND ADMINISTRATION The dosage of Alfentanil HCl injection should be individualized and titrated to the desired effect in each patient according to body weight, physical status, underlying pathological condition, use of other drugs, and type and duration of surgical procedure and anesthesia. In obese patients (more than 20% above ideal total body weight), the dosage of Alfentanil HCl injection should be determined on the basis of lean body weight. The dose of Alfentanil HCl injection should be reduced in elderly or debilitated patients (see PRECAUTIONS). Vital signs should be monitored routinely. See Dosage Guidelines for the use of Alfentanil HCl injection: 1) by incremental injection as an analgesic adjunct to anesthesia with barbiturate/nitrous oxide/oxygen for short surgical procedures (expected duration of less than one hour); 2) by continuous infusion as a maintenance analgesic with nitrous oxide/oxygen for general surgical procedures; and 3) by intravenous injection in anesthetic doses for the induction of anesthesia for general surgical procedures with a minimum expected duration of 45 minutes; and 4) by intravenous injection as the analgesic component for monitored anesthesia care (MAC). page 6 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda DOSAGE GUIDELINES DOSAGE SHOULD BE INDIVIDUALIZED AND TITRATED FOR USE DURING GENERAL ANESTHESIA SPONTANEOUSLY BREATHING/ASSISTED VENTILATION Induction of Analgesia: 8 to 20 mcg/kg Maintenance of Analgesia: 3 to 5 mcg/kg q 5 to 20 min or 0.5 to 1 mcg/kg/min Total dose: 8 to 40 mcg/kg ASSISTED OR CONTROLLED VENTILATION Induction of Analgesia: 20-50 mcg/kg Maintenance of Analgesia: 5-15 mcg/kg q 5-20 min Total dose: Up to 75 mcg/kg Incremental Injection (To attenuate response to laryngoscopy and intubation) Continuous Infusion (To provide attenuation of response to intubation and incision) Infusion rates are variable and should be titrated to the desired clinical effect. SEE INFUSION DOSAGE GUIDELINES BELOW. Induction of Analgesia: 50 to 75 mcg/kg Maintenance of Analgesia: 0.5 to 3 mcg/kg/min (Average rate 1 to 1.5 mcg/kg/min) Total dose: Dependent on duration of procedure Anesthetic Induction Induction of Anesthesia: 130 to 245 mcg/kg Maintenance of Anesthesia: 0.5 to 1.5 mcg/kg/min or general anesthetic Total dose: Dependent on duration of procedure At these doses, truncal rigidity should be expected and a muscle relaxant should be utilized. Administer slowly (over 3 minutes). Concentration of inhalation agents reduced by 30 to 50% for initial hour. MONITORED ANESTHESIA Induction of MAC: 3 to 8 mcg/kg CARE (MAC) Maintenance of MAC: 3 to 5 mcg/kg q 5 to 20 min or 0.25 to 1 mcg/ For sedated and responsive, kg/min spontaneously breathing patients) Total dose: 3 to 40 mcg/kg page 7 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Continuous Infusion: 0.5 to 3 mcg/kg/min administered with nitrous oxide/oxygen in patients undergoing general surgery. Following an anesthetic induction dose of Alfentanil HCl injection , infusion rate requirements are reduced by 30 to 50% for the first hour of maintenance. Changes in vital signs that indicate a response to surgical stress or lightening of anesthesia may be controlled by increasing the alfentanil to a maximum of 4 mcg/kg/min and/or administration of bolus doses of 7 mcg/kg. If changes are not controlled after three bolus doses given over a five minute period, a barbiturate, vasodilator, and/or inhalation agent should be used. Infusion rates should always be adjusted downward in the absence of these signs until there is some response to surgical stimulation. Rather than an increase in infusion rate, 7 mcg/kg bolus doses of Alfentanil HCl injection or a potent inhalation agent should be administered in response to signs of lightening of anesthesia within the last 15 minutes of surgery. Alfentanil HCl injection infusion should be discontinued at least 10 to 15 minutes prior to the end of surgery. page 8 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Usage in Children: Clinical data to support the use of Alfentanil HCl injection in patients under 12 years of age are not presently available. Therefore, such use is not recommended. Premedication: The selection of preanesthetic medications should be based upon the needs of the individual patient. Neuromuscular Blocking Agents: The neuromuscular blocking agent selected should be compatible with the patient’s condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections). In patients administered anesthetic (induction) dosages of Alfentanil HCl injection, it is essential that qualified personnel and adequate facilities are available for the management of intraoperative and postoperative respiratory depression. Also see WARNINGS and PRECAUTIONS sections. For purposes of administering small volumes of Alfentanil HCl injection accurately, the use of a tuberculin syringe or equivalent is recommended. The physical and chemical compatibility of Alfentanil HCl injection have been demonstrated in solution with normal saline, 5% dextrose in normal saline, 5% dextrose in water and Lactated Ringers. Clinical studies of Alfentanil HCl injection infusion have been conducted with Alfentanil HCl injection diluted to a concentration range of 25 mcg/mL to 80 mcg/mL. As an example of the preparation of Alfentanil HCl injection for infusion, 20 mL of Alfentanil HCl injection added to 230 mL of diluent provides 40 mcg/mL solution of Alfentanil. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. SAFETY AND HANDLING Alfentanil HCl injection, USP is supplied in individually sealed dosage forms which pose no known risk to health care providers having incidental contact. Accidental dermal exposure to alfentanil should be treated by rinsing the affected area with water. Storage: Store at 20° to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Protect from light. HOW SUPPLIED Alfentanil HCl injection, USP for intravenous use. Each mL contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and WFI q.s. Alfentanil HCl injection, USP is available as: NDC 17478-067-02, 2 mL Ampule in packages of 10 NDC 17478-067-05, 5 mL Ampule in packages of 10 NDC 17478-067-10, 10 mL Ampule in packages of 5 NDC 17478-067-20, 20 mL Ampule in packages of 5 U.S. Patent No. 4167,574 May 1995, November 1995 company logo Manufactured by: Akorn, Inc. Lake Forest, IL 60045 AFA0N Rev. 04/13 page 9 of 8 Reference ID: 3797278 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:21.760973	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019353s019lbl.pdf', 'application_number': 19353, 'submission_type': 'SUPPL ', 'submission_number': 19}
11,473	NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 4 Baxter OSMITROL Injection (Mannitol Injection, USP) in AVIVA Plastic Container For Therapeutic Use Only Description Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. Composition, osmolarity, and pH are shown in Table 1. Composition Table 1 Size (mL) Mannitol, USP (g/L) Osmolarity (mOsmol/L) (calc) pH 5% OSMITROL Injection (5% Mannitol Injection, USP) 1000 50 274 5.5 (4.5 TO 7.0) 500 10% OSMITROL Injection (10% Mannitol Injection, USP) 1000 100 549 5.5 (4.5 TO 7.0) 15% OSMITROL Injection (15% Mannitol Injection, USP) 500 150 823 5.5 (4.5 TO 7.0) 250 20% OSMITROL Injection (20% Mannitol Injection, USP) 500 200 1098 5.5 (4.5 TO 7.0) Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L. Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 5 Mannitol The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for the attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not secreted by the tubule, and is pharmacologically inert. Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 6 and chloride by elevating the osmolarity of the glomerular filtrate. This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure. Indications and Usage Osmitrol Injection (Mannitol Injection, USP) is indicated for: The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established; The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass; The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means, and promoting the urinary excretion of toxic substances. Contraindications Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with: Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal damage or dysfunction after institution of mannitol therapy, including increasing oliguria and azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy. Warnings In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and Administration). A second test dose may be tried if there is an inadequate response, but no more than two test doses should be attempted. The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration. If urine output continues to decline during mannitol infusion, the patient’s clinical status should be closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart failure. Excessive loss of water and electrolytes may lead to serious imbalances. With continued administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte measurements, including sodium and potassium, are therefore, of vital importance in monitoring the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 7 infusion of mannitol. Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during mannitol infusion. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. The cardiovascular status of the patient should be carefully evaluated before rapidly administrating mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia. By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolemia. Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool to room temperature before reinspection for crystals. Administer intravenously using sterile, filter- type administration set. Laboratory Tests Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 8 The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring. Drug Interaction Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol Injection (Mannitol Injection, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also not known whether mannitol can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. Usage in Children Dosage requirements for patients 12 years of age and under have not been established. Geriatric Use Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 9 to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Extensive use of mannitol over the last several decades has produced recorded adverse events, in a variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions have occurred with any great frequency nor with any security in attributing them to mannitol. The inability to clearly exclude the drug related nature of such events in these isolated reports prompts the necessity to list the reactions that have been observed in patients during or following mannitol infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension, tachycardia, fever and angina-like chest pains. Of far greater clinical significance is a variety of events that are related to inappropriate recognition and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner. Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or aggravate preexisting hyponatremia. If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred vision, convulsions and congestive cardiac failure. These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of degree of renal failure with a test dose response to mannitol when indicated; evaluation of hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration; and evaluation of renal, cardiac and pulmonary function at the onset of therapy. Dosage and Administration Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion. The total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 10 and dosage is only a general guide to therapy. Parenteral dug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20% solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if there is an inadequate response, the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will depend upon the fluid requirements of the patient. Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20% solution. Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a prompt and maximal effect. When used preoperatively the dose should be given one to one and one- half hours before surgery to achieve maximal reduction of intraocular pressure before operation. Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a satisfactory reduction in intracranial pressure. Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15% or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary output of the patient. Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of dosage. All injections in AVIVA containers are intended for intravenous administration using sterile equipment. The use of supplemental additive medication is not recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 11 How Supplied Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows: Code Size (mL) NDC Product Name 6E5604 1000 0338-6300-04 5% Osmitrol Injection (5% Mannitol Injection, USP) 6E5613 6E5614 500 1000 0338-6301-03 0338-6301-04 10% Osmitrol Injection (10% Mannitol Injection, USP) 6E5623 500 0338-6302-03 15% Osmitrol Injection (15% Mannitol Injection, USP) 6E5632 6E5633 250 500 0338-6303-02 0338-6303-03 20% Osmitrol Injection (20% Osmitrol Injection) Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 12 ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 13 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 14 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 15 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 16 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 17 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 18 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 19 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 20 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 21 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 22 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 23 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 24 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 25 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). c * D-Glucopyranose monohydrate Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 26 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 27 electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 28 Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum amorality and possible hemorrhage. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 29 reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasations, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size NDC 6E2073 500 mL NDC 0338-6306-03 6E2074 1000 mL NDC 0338-6306-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 30 To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 31 All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 32 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container Description Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2·2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 250 500 Lactated Ringer’s Injection, USP 1000 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 33 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the treatment of lactic acidosis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 34 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Test CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH EVALUATION. Drug Interactions Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Lactated Ringer's Injection, USP. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 35 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis; periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of these signs and symptoms is higher in women during pregnancy. Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of infection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 36 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 37 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 38 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 39 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 40 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 41 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 42 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 43 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 44 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 45 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 46 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 47 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 48 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 49 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 50 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 51 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 52 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 53 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 54 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 55 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 56 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 57 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 58 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 59 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA Plastic Container Description Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Lactate (C3H5NaO3) Osmolarity (mOsmol/L) (calc) pH Sodium Lactate Caloric Content (kcal/L) 500 Sodium Lactate Injection, USP (M/6 Sodium Lactate) 1000 18.7 334 6.5 (6.0 to 7.3) 167 167 54 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 60 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications None known Warnings Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result in sodium retention. Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis. Precautions General This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 61 Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium Lactate) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Lactate Injection, USP (M/6 Sodium Lactate). Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6 Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 62 Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 63 How Supplied Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E1803 500 0338-6311-03 6E1804 1000 0338-6311-04 EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 64 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 65 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 66 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 67 edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 68 Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 69 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 70 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 71 Baxter Ringer’s Injection, USP in AVIVA Plastic Container Description Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration are shown in Table 1. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Calcium Chloride, USP (CaCl2·2H2O) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride 500 Ringer’s Injection, USP 1000 8.6 0.33 0.3 309 5.5 (5.0 to 7.5) 147.5 4 4.5 156 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 72 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 73 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer’s Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 74 Geriatric Use Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2303 500 NDC 0338-6312-03 6E2304 1000 NDC 0338-6312-04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 75 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 76 Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 77 Baxter Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no antimicrobial agents. The pH is 4.0 (3.5 to 6.5). c D-Glucopyranose monohydrate Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium, 4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 78 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 79 Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Ringer's and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5% Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is administered to a nursing woman. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 80 Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of ringer's and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 81 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2064 1000 NDC 0338-6313-04 6E2063 500 NDC 0338-6313-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 82 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter Healthcare International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 83 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 84 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 85 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 86 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 87 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 88 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 89 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 90 Baxter Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) ** Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Chloride Caloric Content (kcal/L) 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP 500 1000 25 4.5 280 4.5 (3.2 to 6.5) 77 77 85 5% Dextrose and 0.2% Sodium Chloride Injection, USP 250 500 1000 50 2 321 4.0 (3.2 to 6.5) 34 34 170 5% Dextrose and 0.33% Sodium Chloride Injection, USP 250 500 1000 50 3.3 365 4.0 (3.2 to 6.5) 56 56 170 5% Dextrose and 0.45% Sodium Chloride Injection, USP 250 500 1000 50 4.5 406 4.0 (3.2 to 6.5) 77 77 170 5% Dextrose and 0.9% Sodium Chloride Injection, USP 250 500 1000 50 9 560 4.0 (3.2 to 6.5) 154 154 170 10% Dextrose and 0.9% Sodium Chloride Injection, USP 500 1000 100 9 813 4.0 (3.2 to 6.5) 154 154 340 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 91 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 92 Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Dextrose injections with low electrolyte concentrations should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant hypokalemia. In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 93 Drug Interactions Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 94 at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows: Code Size (mL) NDC Product Name 6E1023 6E1024 500 1000 0338-6315-03 0338-6315-04 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 95 6E1092 6E1093 6E1094 250 500 1000 0338-6310-02 0338-6310-03 0338-6310-04 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1082 6E1083 6E1084 250 500 1000 0338-6309-02 0338-6309-03 0338-6309-04 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1072 6E1073 6E1074 250 500 1000 0338-6308-02 0338-6308-03 0338-6308-04 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1062 6E1063 6E1064 250 500 1000 0338-6305-02 0338-6305-03 0338-6305-04 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E1163 6E1164 500 1000 0338-6314-03 0338-6314-04 10% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 96 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 97 Baxter PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 98 Clinical Pharmacology PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148 Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 99 In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 100 Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 101 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2534 1000 NDC 0338-6316-04 6E2533 500 NDC 0338-6316-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 102 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 103 Baxter PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0). PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 21 lcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 104 Clinical Pharmacology PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with blood or blood components. It may be administered prior to or following the infusion of blood through the same administration set (i.e., as a priming solution), added to or infused concurrently with blood components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood components. Contraindications None known Warnings PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 105 overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 106 A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elkerly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 107 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2544 1000 NDC 0338-6317-04 6E2543 500 NDC 0338-6317-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 108 To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 109 Baxter PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 110 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 111 PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 112 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 113 selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 114 6E2573 500 NDC 0338-6318-03 6E2574 1000 NDC 0338-6318-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 115 Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 116 Baxter PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate (C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 117 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 118 administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium ions may result in sodium or potassium retention. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 119 Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 120 In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 121 of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2564 NDC 0338-6319-04 500 6E2563 NDC 0338-6319-03 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 122 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 123 Baxter PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type 2, USP) in AVIVA Plastic Container Description PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl); 89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 124 PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 125 Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA- LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 126 Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 127 Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2504 1000 NDC 0338-6320-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 128 To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 129 Baxter PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric acid. c D-Glucopyranose monohydrate PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 130 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or gluconate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 131 The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 132 Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 133 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Size (mL) Code NDC 1000 6E2584 NDC 0338-6321-04 500 6E2583 NDC 0338-6321-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 134 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 135 XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 136 Baxter 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and 12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq chloride, 23 mEq lactate and 3 mEq phosphate as HPO4 =. The osmolarity is 348 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 137 The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 138 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Do not administer simultaneously with blood. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 139 Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemmorhage. Geriatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 140 Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 141 How Supplied 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2102 250 NDC 0338-6322-02 6E2103 500 NDC 0338-6322-03 6E2104 1000 NDC 0338-6322-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 142 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 143 Baxter Potassium Chloride in 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. HO O OH • H O OH OH HO 2 * D-Glucose monohydrate Composition (g/L) Ionic Concentration (mEq/L) Table 1 Potassium Chloride in 5% Dextrose Injection, USP mEq Potassium Size (mL) *Dextrose Hydrous, USP Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Potassium Chloride Caloric Content (kcal/L) 10 mEq 1000 50 0.75 272 4.5 (3.5 to 6.5) 10 10 170 20 mEq 1000 50 1.5 293 4.5 (3.5 to 6.5) 20 20 170 30 mEq 1000 50 2.24 312 4.5 (3.5 to 6.5) 30 30 170 40 mEq 1000 20 mEq 500 50 3 333 4.5 (3.5 to 6.5) 40 40 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 144 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwarp is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not administer simultaneously with blood. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 145 The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose Injection, USP may result in potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose Injection, USP. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 146 Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 147 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1124 1000 0338-6323-04 10 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1134 1000 0338-6324-04 20 mEq Potassium Chloride in 5% Dextrose Injection, USP This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 148 6E1174 1000 0338-6325-04 30 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1264 1000 0338-6326-04 40 mEq Potassium Chloride in 5% Dextrose Injection, USP 6E1263 500 0338-6326-03 20 mEq Potassium Chloride in 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 149 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 150 Baxter Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid and electrolyte replenishment in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1. Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (Calc.) pH Sodium Potassium Chloride 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 1.5 348 5.5 (3.5 to 6.5) 154 20 174 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 1000 9 3 388 5.5 (3.5 to 6.5) 154 40 194 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 151 (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride Injection, USP may result in sodium or potassium retention. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 152 Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 153 Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Geriatric Use Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 154 Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1764 1000 0338-6327-04 20 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP 6E1984 1000 0338-6328-04 40 mEq/L Potassium Chloride in 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C (104º F) does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 155 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 156 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 157 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 158 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 159 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 160 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 161 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 162 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 163 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 164 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 165 Baxter Sodium Chloride Injection, USP in AVIVA Plastic Container Description Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below. 0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride. 0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 166 0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis procedures. Contraindications None known. Warnings Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 167 Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 168 As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied The available sizes of each injection in AVIVA plastic containers are shown below: Code Size (mL) NDC Product Name 6E1313 500 0338-6333-03 0.45% Sodium Chloride Injection, USP 6E1314 1000 0338-6333-04 6E1356 250 0338-6333-02 6E1322 250 0338-6304-02 0.9% Sodium Chloride Injection, USP 6E1323 500 0338-6304-03 6E1324 1000 0338-6304-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C/77°F); brief exposure up to 40°C(104°F) does not adversely affect the product. Directions for Use of AVIVA plastic container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 169 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in-use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. For Product Information 1-800-833-0303 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 170 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 171 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 172 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 173 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 174 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 175 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 176 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 177 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 178 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 179 Baxter Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA Plastic Container Description Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 180 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. Composition (g/L) Ionic Concentration (mEq/L) Table 1 Size (mL) Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) pH Sodium Potassium Chloride Caloric Content (kcal/L) Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 2 0.75 341 4.5 (3.5 to 6.5) 34 10 44 170 20 mEq 10 mEq 1000 500 50 2 1.5 361 4.5 (3.5 to 6.5) 34 20 54 170 30 mEq 1000 50 2 2.24 381 4.5 (3.5 to 6.5) 34 30 64 170 40 mEq 1000 50 2 3 401 4.5 (3.5 to 6.5) 34 40 74 170 Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP mEq Potassium 20 mEq 10 mEq 1000 500 50 3.3 1.5 405 4.5 (3.5 to 6.5) 56 20 76 170 30 mEq 1000 50 3.3 2.24 425 4.5 (3.5 to 6.5) 56 30 86 170 40 mEq 1000 50 3.3 3 446 4.5 (3.5 to 6.5) 56 40 96 170 Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP mEq Potassium 10 mEq 1000 50 4.5 0.75 426 4.5 (3.5 to 6.5) 77 10 87 170 20 mEq 10 mEq 1000 500 50 4.5 1.5 447 4.5 (3.5 to 6.5) 77 20 97 170 30 mEq 1000 50 4.5 2.24 466 4.5 (3.5 to 6.5) 77 30 107 170 40 mEq 1000 50 4.5 3 487 4.5 (3.5 to 6.5) 77 40 117 170 Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP mEq Potassium 20 mEq 1000 50 9 1.5 601 4.5 (3.5 to 6.5) 154 20 174 170 40 mEq 1000 50 9 3 641 4.5 (3.5 to 6.5) 154 40 194 170 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 181 HO O OH • H O OH OH HO 2 ** D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes and calories. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 182 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Injections containing carbohydrates with low electrolyte concentration should not be administered simultaneously with blood through the same administration set because of the possibility of pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not administer simultaneously with blood. The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium retention. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 183 Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 184 Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 185 How Supplied Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC Product Name 6E1604 1000 0338-6334-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1614 6E1613 1000 500 0338-6335-04 0338-6335-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1624 1000 0338-6336-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1634 1000 0338-6337-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.2% Sodium Chloride Injection, USP 6E1474 6E1473 1000 500 0338-6348-04 0338-6348-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1484 1000 0338-6349-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1494 1000 0338-6350-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.33% Sodium Chloride Injection, USP 6E1644 1000 0338-6329-04 10 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1654 6E1653 1000 500 0338-6330-04 0338-6330-03 20 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1664 1000 0338-6331-04 30 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E1674 1000 0338-6332-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.45% Sodium Chloride Injection, USP 6E2434 1000 0338-6342-04 20 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP 6E2454 1000 0338-6343-04 40 mEq/L Potassium Chloride in 5% Dextrose and 0.9% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 186 Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 187 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 188 Baxter 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA Plastic Container Description 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5). c D-Glucopyranose monohydrate 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate, and 15 mEq phosphate as HPO4 =. The osmolarity is 402 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 189 The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen, and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 190 dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overloading causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or potassium retention. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) is not for use in the treatment of lactic acidosis. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution. Excess administration may result in metabolic alkalosis. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 191 Carcinogenesis, mutagenesis, impairment of fertility Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION (MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING MOTHER. Pediatric Use Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. Geriatric Use Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 192 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2112 250 NDC 0338-6338-02 6E2113 500 NDC 0338-6338-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 193 6E2114 1000 NDC 0338-6338-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 194 * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 195 Baxter 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container Description 3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. The pH may have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in Table 1. Composition (g/L) Ionic Concentration (mEq/L) Table 1 size (mL) Sodium Chloride USP (NaCl) Sodium Chloride Osmolarity (mOsmol/L) (calc) pH 3% Sodium Chloride Injection, USP 500 30 513 513 1027 5.5 (4.5 to 7.0) 5% Sodium Chloride Injection, USP 500 50 856 856 1711 5.5 (4.5 to 7.0) Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 196 Clinical Pharmacology 3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Indications and Usage 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. Contraindications None known Warnings 3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage. 3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection, USP may result in sodium retention. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 197 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3% and 5% Sodium Chloride Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5% Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is administered to a nursing woman. Pediatric Use Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 198 Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied 3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows: Code Size (mL) NDC Product Name 6E1353 500 0338-6339-03 3% Sodium Chloride Injection, USP 6E1373 500 0338-6340-03 5% Sodium Chloride Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 199 Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 200 Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 201 Baxter PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA Plastic Container Description PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic, hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains 234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0). PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage. The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 202 PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent. Contraindications None known Warnings PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be administered simultaneously with blood through the same administration set because of the possibility of hemolysis. The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 203 Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with caution. Excess administration may result in metabolic alkalosis. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). Carcinogenesis, mutagenesis, impairment of fertility Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA- LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 204 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is administered to a nursing woman. Pediatric Use Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Geriatric Use Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 205 All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic containers is available as shown below: Code Size (mL) NDC 6E2524 1000 NDC 0338-6341-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 206 To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 207 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA Plastic Container Description Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Composition (g/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5NaO3) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc.) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 208 HO O OH • H O OH OH HO 2 * D-Glucose monohydrate The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. Ionic Concentration (mEq/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Sodium Potassium Calcium Chloride Lactate Caloric Content (kcal/L) 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 ** The chemical structure for Dextrose Hydrous, USP is shown below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 209 The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. Clinical Pharmacology Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn product. Warnings Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 210 congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the treatment of lactic acidosis. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions General Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Drug Interactions Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 211 Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly neonates and low birth weight infants. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 212 from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of final filter is recommended during administration of fall parenteral solutions, where possible. Do not administer unless solution is clear and seal is intact. All injections in AVIVA plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below: Code Size (mL) NDC Product Name 6E2224 1000 NDC 0338-6344-04 20 mEq/L Potassium Chloride in Lactated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 213 Ringer’s and 5% Dextrose Injection, USP 6E2244 1000 NDC 0338-6345-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not adversely affect the product. Directions for Use of AVIVA Plastic Container To Open Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration Caution: Do not use plastic containers in series connections. Caution: Use only with a non-vented set or a vented set with the vent closed. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100, 16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091, 16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055, 17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065, 17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029, 19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022 Page 214 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA * Bar Code Position Only XXXXXXXXX ©Copyright XXXX Baxter Healthcare Corporation All rights reserved. X-XX-XX-XXX Rev. August 2005 Baxter and AVIVA are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:21.848366	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 19308, 'submission_type': 'SUPPL ', 'submission_number': 22}
11,481	07-19-63-782 Baxter Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX Plastic Container DESCRIPTION Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous, USP; 600 mg Sodium Chloride, USP (NaCl); 310 mg Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride, USP (CaCl2 • 2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5). structural formula Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L (calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. The caloric content is 180 kcal/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s and 5% Dextrose Injection, USP, through the same infusion line (e.g., via Y- connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s and 5% Dextrose Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s and 5% Dextrose Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Solutions containing dextrose should be used with caution, if at all, in patients with known allergy to corn or corn products. Depending on the volume and rate of infusion, the intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactate is a substrate for gluconeogenesis. Administration of solutions containing dextrose and lactate should be used with caution in patients with impaired glucose tolerance and diabetes mellitus, as it may result in hyperglycemia. Hyperglycemia has been implicated in increasing cerebral ischemic brain damage and impairing recovery after acute ischemic strokes. Caution is recommended in using dextrose-containing solutions is such patients. Early hyperglycemia has been associated with poor outcomes in patients with severe traumatic brain injury. Dextrose-containing solutions should, therefore, be used with caution in patients with head injury, in particular during the first 24 hours following the trauma. If hyperglycemia occurs, the rate of dextrose administration should be reduced and/or insulin administered, or the insulin dose adjusted. Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia (i.e., high lactose levels) can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s and 5% Dextrose Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The osmolarity of Lactated Ringer’s and 5% Dextrose Injection, USP is 525 mOsmol/L (calc). Administration of substantially hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Pediatric Use Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of lactated ringer’s and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In newborns, the risk of hyperglycemia due to infusion of dextrose-containing solutions appears to be greater with lower birth weight. In these patients, hyperglycemia and increased serum osmolarity have been associated with an increased risk of intraventricular cerebral hemorrhage. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s and 5% Dextrose Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with lithium. Because of its potassium content, Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s and 5% Dextrose Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, nausea and pyrexia. General Disorders and Administration Site Conditions: Infusion site reactions, including infusion site pruritus, infusion site erythema, infusion site anesthesia (numbness). Class Reactions -Other manifestations of hypersensitivity/infusion reactions: decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, laryngeal edema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, anxiety, headache, and sneezing -Hyperkalemia -Hypervolemia 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -Other infusion site reactions: infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pain, infusion site burning. Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s and 5% Dextrose Injection, USP may lead to fluid and sodium overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. Excessive administration of a dextrose-containing solution may lead to hyperglycemia, hyperosmolarity, osmotic diuresis, and dehydration. When assessing overdose, any additives in the solution must also be considered. The effects of overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. The infusion rate should not exceed the patient’s ability to utilize glucose in order to avoid hyperglycemia. 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. See Precautions, Pediatric Use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact. When making additions to Lactated Ringer’s and 5% Dextrose Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s and 5% Dextrose Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s and 5% Dextrose Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX plastic containers is available as follows: Code Size NDC 2B2073 500 mL NDC 0338-0125-03 2B2074 1000 mL NDC 0338-0125-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Directions for use of VIAFLEX plastic container For Information on Risk of Air Embolism - see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963782 07-19-63-782 Rev. October 2011 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 11 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-783 Baxter Lactated Ringer’s Injection, USP in VIAFLEX Plastic Container DESCRIPTION Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Composition (g/L) Ionic Composition (mEq/L) Caloric Content (kcal/L) Size (mL) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3H5 NaO3 ) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2•2H2O) Osmolarity (mOsmol/L) (calc) pH Sodium Potassium Calcium Chloride Lactate Lactated 250 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 Ringer’s 500 Injection, USP 1000 The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Lactated Ringer’s Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. Lactated Ringer’s Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Depending on the volume and the rate of infusion, the intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Lactate is a substrate for gluconeogenesis. This should be taken into account when Lactated Ringer’s Injection, USP is used in patients with type 2 diabetes. Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with lithium. Because of its potassium content, Lactated Ringer’s Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, mutagenesis, impairment of fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, nausea, anxiety, pyrexia, headache Metabolism and Nutrition Disorders: Hyperkalemia General Disorders and Administration Site Conditions: Infusion site reactions, including phlebitis, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site burning 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Class Reactions Hypersensitivity reactions, including, laryngeal edema and sneezing Hypervolemia Infusion site reactions, including Infection at the site of injection, extravasation, and infusion site anesthesia (numbness) Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s Injection, USP may lead to fluid and sodium overload with a risk of edema (peripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Lactated Ringer’s Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s Injection, USP in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B2322 250 0338-0117-02 2B2323 500 0338-0117-03 2B2324 1000 0338-0117-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963783 07-19-63-783 Rev. October 2011 BAXTER, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-784 Baxter Lactated Ringer’s Injection, USP in AVIVA Plastic Container DESCRIPTION Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in single dose containers for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH nominal (range) Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Chloride, USP, (NaCl) Sodium Lactate, (C3 H5 NaO3 ) Potassium Chloride, USP, (KCl) Calcium Chloride, USP (CaCl2 ·2H2O) Sodium Potassium Calcium Chloride Lactate Lactated Ringer’s Injection, USP 250 6 3.1 0.3 0.2 273 6.5 (6.0 to 7.5) 130 4 2.7 109 28 9 500 1000 The flexible container is made with non-latex plastic materials specially designed for a wide range of parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene. For example, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of paclitaxel. In addition, the AVIVA container system is compatible with and appropriate for use in the admixture and administration of all drugs deemed compatible with existing polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or other plasticizers. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The suitability of the container materials has been established through biological evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers. These tests confirm the biological safety of the container system. The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The container does not require entry of external air during administration. The container has two ports: one is the administration outlet port for attachment of an intravenous administration set and the other port has a medication site for addition of supplemental medication (See Directions for Use). The primary function of the overwrap is to protect the container from the physical environment. CLINICAL PHARMACOLOGY Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the patient. Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing agent. CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Lactated Ringer’s Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Lactated Ringer’s Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Although Lactated Ringer’s Injection, USP has a potassium concentration similar to the concentration in plasma, it is insufficient to produce a useful effect in case of severe potassium deficiency; therefore, it should not be used for this purpose. Lactated Ringer’s Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Lactated Ringer’s Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Hypersensitivity reactions are reported more frequently during pregnancy. Depending on volume and rate of infusion, the intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injections. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with hyperkalemia or conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns) and in patients with cardiac disease. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Lactated Ringer’s Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Lactated Ringer’s Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. Lactate is a substrate for gluconeogenesis. This should be taken into account when Lactated Ringer’s Injection, USP is used in patients with type 2 diabetes. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Lactated Ringer’s Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with lithium. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Because of its potassium content, Lactated Ringer’s Injection, USP should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Caution is advised when administering Lactated Ringer’s Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Lactated Ringer’s Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s Injection, USP should be given to a pregnant woman only if clearly needed. For Hypersensitivity Reactions During Pregnancy – see Warnings Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Lactated Ringer’s Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Lactated Ringer’s Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lactated Ringer’s Injection, USP is administered to a nursing mother. ADVERSE REACTIONS 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, nausea, anxiety, pyrexia, headache Metabolism and Nutrition Disorders: Hyperkalemia General Disorders and Administration Site Conditions: Infusion site reactions, including phlebitis, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site burning Class Reactions Hypersensitivity reactions, including, laryngeal edema and sneezing Hypervolemia Infusion site reactions, including Infection at the site of injection, extravasation, and infusion site anesthesia (numbness) Overdose An excessive volume or too high a rate of administration of Lactated Ringer’s Injection, USP may lead to fluid and sodium overload with a risk of edema (peripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. When assessing an overdose, any additives in the solution must also be considered. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in AVIVA plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Lactated Ringer’s Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Lactated Ringer’s Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Lactated Ringer’s Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows: Code Size (mL) NDC 6E2322 250 0338-6307-02 6E2323 500 0338-6307-03 6E2324 1000 0338-6307-04 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA For Bar Code Position Only 071963784 07-19-63-784 Rev. October 2011 Baxter and AVIVA are trademarks of Baxter International Inc. 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-785 Baxter Sodium Lactate Injection, USP (M/6 Sodium Lactate) in VIAFLEX Plastic Container DESCRIPTION Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1. Table 1 Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc) pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Lactate (C3H5NaO3) Sodium Lactate Sodium Lactate Injection, USP (M/6 Sodium Lactate) 500 18.7 334 6.5 (6.0 to 7.3) 167 167 54 1000 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent. CONTRAINDICATIONS Sodium Lactate Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. WARNINGS Sodium Lactate Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Depending on the volume and rate of infusion, the intravenous administration of these injections can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid- base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Excessive administration of Sodium Lactate Injection, USP may result in hypokalemia. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium retention, fluid overload, or edema. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. Sodium Lactate Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Sodium Lactate Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. Lactate is a substrate for gluconeogenesis. This should be taken into account when Sodium Lactate Injection, USP is used in patients with type 2 diabetes. Pediatric Use Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium lactate solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Geriatric Use Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Caution is advised when administering Sodium Lactate Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Sodium Lactate Injection USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Sodium Lactate Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine), and dextroamphetamine (dexamphetamine) sulfate may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Sodium Lactate Injection, USP to patients treated with lithium. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Lactate Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate Injection, USP should be given to a pregnant woman only if clearly needed. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Sodium Lactate Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions manifested by: blood pressure decreased, pyrexia General Disorders and Administration Site Conditions: Infusion site burning Class Reactions Other symptoms of hypersensitivity/infusion reactions: anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, decreased heart rate, tachycardia, respiratory distress, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, flushing, throat irritation, paresthaesias, hypesthesia oral, dysgeusia, nausea, anxiety and headache. Hypervolemia Infusion site reactions, including infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pruritus, infusion site erythema, infusion site pain, infusion site anesthesia (numbness) 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Overdose An excessive volume or too high a rate of administration of Sodium Lactate Injection, USP may lead to fluid and sodium overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. When assessing an overdose, any additives in the solution must also be considered. The effects of an overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and seal is intact. When making additions to Sodium Lactate Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Sodium Lactate Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Sodium Lactate Injection, USP is appropriate. 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Sodium Lactate Injection, USP (M/6 Sodium Lactate) in VIAFLEX plastic container is available as follows: Code Size (mL) NDC 2B1803 500 0338-0129-03 2B1804 1000 0338-0129-04 Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Bar Code Position Only 071963785 07-19-63-785 Rev. October 2011 BAXTER, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 07-19-63-786 Baxter Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in Plastic Container VIAFLEX Plus Container DESCRIPTION Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: Table 1. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added Size (mL) Composition (g/L) Osmolarity (mOsmol/L) (calc.) *Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5 NaO3 ) Potassium Chloride, USP (KCl) Calcium Chloride, USP (CaCl2-2H2 O) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. structural formula 1 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 2. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added pH Ionic Concentration (mEq/L) Caloric Content (kcal/L) Sodium Potassium Calcium Chloride Lactate 20 mEq 5.0 (3.5 to 6.5) 130 24 3 129 28 170 40 mEq 5.0 (3.5 to 6.5) 130 44 3 149 28 170 The VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2- ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. INDICATIONS AND USAGE Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. 2 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CONTRAINDICATIONS As for other calcium-containing infusion solutions, concomitant administration of ceftriaxone and Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in newborns (≤ 28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone-calcium salt precipitation in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including Potasssium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP, through the same infusion line (e.g., via Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed between infusions with a compatible fluid. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with a known hypersensitivity to sodium lactate. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is contraindicated in patients with hyperkalemia. WARNINGS Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is not for use for the treatment of lactic acidosis or severe metabolic acidosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with citrate anticoagulated/preserved blood through the same administration set because of the likelihood of coagulation. The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Solutions containing dextrose should be used with caution, if at all, in patients with known allergy to corn or corn products. Depending on the volume and rate of infusion, the intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, pulmonary edema or acid-base imbalance. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. 3 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. Clinical evaluation and periodic laboratory determinations may be necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient or the rate of administration warrants such evaluation. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions predisposing to hyperkalemia (such as severe renal impairment or adrenocortical insufficiency, acute dehydration, or extensive tissue injury or burns), in patients with cardiac disease, and in patients treated with products that increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with alkalosis or at risk for alkalosis. Because lactate is metabolized to bicarbonate, administration may result in, or worsen, metabolic alkalosis. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with severe renal impairment, hypervolemia, overhydration, or conditions that may cause sodium and/or potassium retention, fluid overload, or edema. Potassium salts should never be administered by IV push. PRECAUTIONS Do not connect flexible plastic containers in series in order to avoid air embolism due to possible residual air contained in the primary container. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. 4 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Lactate is a substrate for gluconeogenesis. Administration of solutions containing dextrose and lactate should be used with caution in patients with impaired glucose tolerance and diabetes mellitus, as it may result in hyperglycemia. Hyperglycemia has been implicated in increasing cerebral ischemic brain damage and impairing recovery after acute ischemic strokes. Caution is recommended in using dextrose-containing solutions in such patients. Early hyperglycemia has been associated with poor outcomes in patients with severe traumatic brain injury. Dextrose-containing solutions should, therefore, be used with caution in patients with head injury, in particular during the first 24 hours following the trauma. If hyperglycemia occurs, the rate of dextrose administration should be reduced and/or insulin administered, or the insulin dose adjusted. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be administered with particular caution, if at all, to patients with conditions associated with increased lactate levels or impaired lactate utilization, such as severe hepatic insufficiency. Hyperlactatemia (i.e., high lactate levels) can develop in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. In addition Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may not produce its alkalinizing action in patients with severe hepatic insufficiency, since lactate metabolism may be impaired. The osmolarity of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is 565 mOsmol/L (calc) for 20 mEq potassium added and 605 mOsmol/L (calc) for 40 mEq potassium added. Administration of substantially hypertonic solutions may cause venous irritation, including phlebitis. Hyperosmolar solutions should be administered with caution, if at all, to patients with hyperosmolar states. Solutions containing calcium salts should be used with caution in patients with hypercalcemia or conditions predisposing to hypercalemia, such as patients with severe renal impairment and granulomatous diseases associated with increased calcitriol synthesis such as sarcoidosis, calcium renal calculi or history of such calculi. 5 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pediatric Use Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well- controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. In newborns, the risk of hyperglycemia due to infusion of dextrose-containing solutions appears to be greater with lower birth weight. In these patients, hyperglycemia and increased serum osmolarity have been associated with an increased risk of intraventricular cerebral hemorrhage. Lactate-containing solutions should be administered with particular caution to neonates and infants less than 6 months of age. Geriatric Use Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Drug Interactions Ceftriaxone – see Contraindications Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs that may increase the risk of sodium and fluid retention, such as corticosteroids. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with drugs for which renal elimination is pH dependent. Due to the alkalinizing action of lactate (formation of bicarbonate), Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may interfere with the elimination of such drugs. - Renal clearance of acidic drugs such as salicylates and barbiturates may be increased. 6 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda - Renal clearance of alkaline drugs, such as sympathomimetrics (e.g., ephedrine, pseudoephedrine) and dextroamphetamine (dexamphetamine) sulfate, may be decreased. Renal clearance of lithium may also be increased. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with lithium. Because of its potassium content, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be avoided in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine. Administration of potassium in patients treated with such medications can produce severe and potentially fatal hyperkalemia, particularly in patients with severe renal insufficiency. Caution is advised when administering Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients treated with thiazide diuretics or vitamin D, as these can increase the risk of hypercalcemia. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. Studies to evaluate the possible impairment of fertility have not been performed. 7 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Labor and Delivery Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC). Immune System Disorders: Hypersensitivity/infusion reactions, including anaphylactic/anaphylactoid reactions, and the following manifestations: angioedema, chest pain, chest discomfort, bronchospasm, dyspnea, cough, urticaria, rash, pruritus, erythema, nausea and pyrexia. General Disorders and Administration Site Conditions: Infusion site reactions, including infusion site pruritus, infusion site erythema, infusion site anesthesia (numbness). Class Reactions -Other manifestations of hypersensitivity/infusion reactions: decreased heart rate, tachycardia, blood pressure decreased, respiratory distress, flushing, throat irritation, paresthesias, hypoesthesia oral, dysgeusia, anxiety and headache -Hyperkalemia -Hypervolemia -Other infusion site reactions: infection at the site of injection, phlebitis, extravasation, infusion site inflammation, infusion site swelling, infusion site rash, infusion site pain, infusion site burning Overdose An excessive volume or too high a rate of administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may lead to fluid and sodium 8 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda overload with a risk of edema (pheripheral and/or pulmonary), particularly when renal sodium excretion is impaired. Excessive administration of lactate may lead to metabolic alkalosis. Metabolic alkalosis may be accompanied by hypokalemia. Excessive administration of potassium may lead to the development of hyperkalemia, especially in patients with severe renal impairment. Excessive administration of calcium salts may lead to hypercalcemia. Excessive administration of a dextrose-containing solution may lead to hyperglycemia, hyperosmolarity, osmotic diuresis, and dehydration. When assessing overdose, any additives in the solution must also be considered. The effects of overdose may require immediate medical attention and treatment. DOSAGE AND ADMINISTRATION As directed by a physician. Dosage, rate, and duration of administration are to be individualized and dependent upon the indication for use, the patient’s age, weight, concomitant treatment and clinical condition of the patient as well as laboratory determinations. All injections in VIAFLEX Plus plastic containers are intended for intravenous administration using sterile and nonpyrogenic equipment. After opening the container, the contents should be used immediately and should not be stored for a subsequent infusion. Do not reconnect any partially used containers. The infusion rate should not exceed the patient’s ability to utilize glucose in order to avoid hyperglycemia. As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low weight infants, because of the increased risk of hyperglycemia/hypoglycemia. See Precautions, Pediatric Use. 9 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact. When making additions to Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP, aseptic technique must be used. Mix the solution thoroughly when additives have been introduced. Do not store solutions containing additives. Additives may be incompatible with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. As with all parenteral solutions, compatibility of the additives with the solution must be assessed before addition, by checking for a possible color change and/or the appearance of precipitates, insoluble complexes, or crystals. Before adding a substance or medication, verify that it is soluble and/or stable in water and that the pH range of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is appropriate. The instructions for use of the medication to be added and other relevant literature must be consulted. Additives known or determined to be incompatible should not be used. HOW SUPPLIED Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX Plus plastic containers is available as shown below: Code Size (mL) NDC Product Name 2B2224 1000 0338-0811-04 20 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP 2B2244 1000 0338-0815-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER For Information on Risk of Air Embolism – see Precautions 10 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. 11 Reference ID: 3028897 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *Bar Code Position Only 071963786 07-19-63-786 Revised October 2011 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. Reference ID: 3028897 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.094917	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016679s104,016682s105,016692s095,019367s026lbl.pdf', 'application_number': 19367, 'submission_type': 'SUPPL ', 'submission_number': 26}
11,483	7898531XX TABLETS NOROXIN® (NORFLOXACIN) To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN† and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. † Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1986, 1989, 1999, 2001 All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 2 Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) Microbiology Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MIC's) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 3 Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro minimal inhibitory concentrations (MIC's) of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS.) Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the following criteria: MIC (µg/mL) Interpretation ≤4 Susceptible (S) 8 Intermediate (I) ≥16 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 4 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the following MIC values: Organism MIC range (µg/mL) E. coli ATCC 25922 0.03-0.12 E. faecalis ATCC 29212 2-8 P. aeruginosa ATCC 27853 1-4 S. aureus ATCC 29213 0.5-2 Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the following criteria: Zone diameter (mm) Interpretation ≥17 Susceptible (S) 13-16 Intermediate (I) ≤12 Resistant (R) Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion techniques, the 10-µg norfloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Organism Zone Diameter (mm) E. coli ATCC 25922 28-35 P. aeruginosa ATCC 27853 22-29 S. aureus ATCC 25923 17-28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections: Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS): Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis: Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or * Efficacy for this organism in this organ system was studied in fewer than 10 infections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 5 strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.) Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. (See ADVERSE REACTIONS.) Hypersensitivity/anaphylaxis: Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including norfloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic- associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or largeaxons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or * Based on a patient weight of 50 kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 6 weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Tendon effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including norfloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Norfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including norfloxacin. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe phototoxicity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin. (See ADVERSE REACTIONS.) Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life-threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour ‡ Registered trademark of Bristol-Myers Squibb Company This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 7 period before or within the two-hour period after taking norfloxacin. (See PRECAUTIONS, Drug Interactions.) — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — to avoid undue exposure to excessive sunlight while receiving norfloxacin and to discontinue therapy if phototoxicity occurs. — that some quinolones may increase the effects of theophylline and/or caffeine. (See PRECAUTIONS, Drug Interactions.) — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its plasma half-life. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 8 hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 9 Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity. Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia; psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6- phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 10 In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 3522 — Tablets NOROXIN 400 mg are dark pink, oval shaped, film-coated tablets, coded MSD 705 on one side and NOROXIN on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 11 ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993. 2. National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993. Issued XXXXXXXXXXXXXXX Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.217442	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19384s040,042,043lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 40}
11,484	7898531XX TABLETS NOROXIN® (NORFLOXACIN) To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN† and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. † Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1986, 1989, 1999, 2001 All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 2 Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) Microbiology Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MIC's) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 3 Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro minimal inhibitory concentrations (MIC's) of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS.) Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the following criteria: MIC (µg/mL) Interpretation ≤4 Susceptible (S) 8 Intermediate (I) ≥16 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 4 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the following MIC values: Organism MIC range (µg/mL) E. coli ATCC 25922 0.03-0.12 E. faecalis ATCC 29212 2-8 P. aeruginosa ATCC 27853 1-4 S. aureus ATCC 29213 0.5-2 Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the following criteria: Zone diameter (mm) Interpretation ≥17 Susceptible (S) 13-16 Intermediate (I) ≤12 Resistant (R) Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion techniques, the 10-µg norfloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Organism Zone Diameter (mm) E. coli ATCC 25922 28-35 P. aeruginosa ATCC 27853 22-29 S. aureus ATCC 25923 17-28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections: Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS): Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis: Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or * Efficacy for this organism in this organ system was studied in fewer than 10 infections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 5 strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.) Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. (See ADVERSE REACTIONS.) Hypersensitivity/anaphylaxis: Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including norfloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic- associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or largeaxons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or * Based on a patient weight of 50 kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 6 weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Tendon effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including norfloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Norfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including norfloxacin. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe phototoxicity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin. (See ADVERSE REACTIONS.) Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life-threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour ‡ Registered trademark of Bristol-Myers Squibb Company This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 7 period before or within the two-hour period after taking norfloxacin. (See PRECAUTIONS, Drug Interactions.) — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — to avoid undue exposure to excessive sunlight while receiving norfloxacin and to discontinue therapy if phototoxicity occurs. — that some quinolones may increase the effects of theophylline and/or caffeine. (See PRECAUTIONS, Drug Interactions.) — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its plasma half-life. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 8 hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 9 Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity. Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia; psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6- phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 10 In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 3522 — Tablets NOROXIN 400 mg are dark pink, oval shaped, film-coated tablets, coded MSD 705 on one side and NOROXIN on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 7898531XX 11 ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993. 2. National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993. Issued XXXXXXXXXXXXXXX Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.255385	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19384s040,042,043lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 42}
11,480	Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in Plastic Container VIAFLEX Plus Container 07-19-47-264 Description Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a single dose container for intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown below: The VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the same container as the VIAFLEX plastic container system. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2- ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Clinical Pharmacology Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. Indications and Usage Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of water, electrolytes, and calories or as alkalinizing agents. Contraindications Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. Warnings Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation. The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection. In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP may result in sodium or potassium retention. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. Potassium salts should never be administered by IV push. Precautions Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus. D-Glucose monohydrate Composition (g/L) Ionic Concentration (mEq/L) Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added 5.0 130 24 3 129 28 170 (3.5 to 6.5) 5.0 130 44 3 149 28 170 (3.5 to 6.5) 20 mEq 1000 50 6 3.1 1.79 0.2 565 40 mEq 1000 50 6 3.1 3.28 0.2 605 pH Size (mL) Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP mEq Potassium added 20 mEq 40 mEq * Dextrose Hydrous, USP Sodium Chloride, USP (NaCl) Sodium Lactate, (C3H5Na03) Calcium Chloride, USP (CaCl2·2H20) Potassium Chloride, USP (KCl) Osmolarity (mOsmol/L) (calc.) Lactate Chloride Calcium Potassium Sodium Caloric Content (kcal/L) * The chemical structure for Dextrose Hydrous, USP is shown below: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed. Pediatric Use: Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Geriatric Use: Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Carcinogenesis, mutagenesis, impairment of fertility Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is administered to a nursing mother. Do not administer unless solution is clear and seal is intact. Adverse Reactions Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary. Dosage and Administration As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions, where possible. All injections in VIAFLEX Plus plastic containers are intended for intravenous administration using sterile equipment. Additives may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives. How Supplied Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in VIAFLEX Plus plastic containers is available as shown below: Code Size (mL) NDC Product Name 2B2224 1000 0338-0811-04 20 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP 2B2244 1000 0338-0815-04 40 mEq/L Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product. Directions for use of VIAFLEX Plus Plastic Container Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. To Open Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. If supplemental medication is desired, follow directions below. Preparation for Administration 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. To Add Medication Warning: Additives may be incompatible. To add medication before solution administration 1. Prepare medication site. 2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 3. Mix solution and medication thoroughly. For high density medication such as potassium chloride, squeeze ports while ports are upright and mix thoroughly. To add medication during solution administration 1. Close clamp on the set. 2. Prepare medication site. 3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject. 4. Remove container from IV pole and/or turn to an upright position. 5. Evacuate both ports by squeezing them while container is in the upright position. 6. Mix solution and medication thoroughly. 7. Return container to in use position and continue administration. Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA *For Bar Code Position Only 071947264 07-19-47-264 Rev. March 2005 Baxter, VIAFLEX, and PL 146 are trademarks of Baxter International Inc. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.261950	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019367s021lbl.pdf', 'application_number': 19367, 'submission_type': 'SUPPL ', 'submission_number': 21}
11,486	78985XX TABLETS NOROXIN® (NORFLOXACIN) To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN† and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3- uinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: q Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. † Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1986, 1989, 1999, 2001. MERCK & CO., Inc. All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 2 Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 ours post-dose after two 400-mg doses, unless otherwise indicated: h Renal Parenchyma 7.3 μg/g Prostate 2.5 μg/g Seminal Fluid 2.7 μg/mL Testicle 1.6 μg/g Uterus/Cervix 3.0 μg/g Vagina 4.3 μg/g Fallopian Tube 1.9 μg/g Bile 6.9 μg/mL (after two 200-mg doses) Microbiology Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 3 Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS.) Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations f norfloxacin powder. The MIC values should be interpreted according to the following criteria o : MIC (μg/mL) Interpretation ≤4 Susceptible (S) 8 Intermediate (I) ≥16 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 4 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide he following MIC values: t Organism MIC range (μg/mL) E. coli ATCC 25922 0.03-0.12 E. faecalis ATCC 29212 2-8 P. aeruginosa ATCC 27853 1-4 S . aureus ATCC 29213 0.5-2 Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk hould be interpreted according to the following criteria: s Zone diameter (mm) Interpretation ≥17 Susceptible (S) 13-16 Intermediate (I) ≤12 Resistant (R) Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion techniques, the 10-μg norfloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Organism Zone Diameter (mm) E. coli ATCC 25922 28-35 P. aeruginosa ATCC 27853 22-29 S . aureus ATCC 25923 17-28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections: Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS): Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis: Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or * Efficacy for this organism in this organ system was studied in fewer than 10 infections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 5 strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.) Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. (See ADVERSE REACTIONS.) Hypersensitivity/anaphylaxis: Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including norfloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic- associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or * Based on a patient weight of 50 kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 6 weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Tendon effects: Ruptures of the shoulder, hand, Achilles tendons or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including norfloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Norfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including norfloxacin. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe phototoxicity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin. (See ADVERSE REACTIONS.) Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life-threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two- ‡ Registered trademark of Bristol-Myers Squibb Company This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 7 hour period before or within the two-hour period after taking norfloxacin. (See PRECAUTIONS, Drug Interactions.) — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — to avoid undue exposure to excessive sunlight while receiving norfloxacin and to discontinue therapy if phototoxicity occurs. — that some quinolones may increase the effects of theophylline and/or caffeine. (See PRECAUTIONS, Drug Interactions.) — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 8 Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 9 ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity. Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS); elevated creatine kinase (CK). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 10 Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6- phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine hould represent a steady state of renal function. s Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) 78985XX 11 Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993. 2. National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993. Manufactured for: By: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Issued Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.500666	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019384s046lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 46}
11,487	TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (See WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN∗ and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: Chemical Structure Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal ∗ Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1986, 1989, 1999, 2001 MERCK & CO., Inc. All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 μg/g Prostate 2.5 μg/g Seminal Fluid 2.7 μg/mL Testicle 1.6 μg/g Uterus/Cervix 3.0 μg/g Vagina 4.3 μg/g Fallopian Tube 1.9 μg/g Bile 6.9 μg/mL (after two 200-mg doses) Microbiology Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the following criteria: MIC (μg/mL) Interpretation ≤4 Susceptible (S) 8 Intermediate (I) ≥16 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide Quantitative methods that require measurement of zone diameters also provide reproducible the following MIC values: Organism E. coli ATCC 25922 E. faecalis ATCC 29212 P. aeruginosa ATCC 27853 S. aureus ATCC 29213 MIC range (μg/mL) 0.03-0.12 2-8 1-4 0.5-2 Diffusion Techniques: estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk should be interpreted according to the following criteria: Zone diameter (mm) Interpretation ≥17 Susceptible (S) 13-16 Intermediate (I) ≤12 Resistant (R) Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion techniques, the 10-μg norfloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Organism Zone Diameter (mm) E. coli ATCC 25922 28-35 P. aeruginosa ATCC 27853 22-29 S. aureus ATCC 25923 17-28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections: Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS): Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis: Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy * Efficacy for this organism in this organ system was studied in fewer than 10 infections. 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including * Based on a patient weight of 50 kg. 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium difficile associated diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life-threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two- hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). ‡ Registered trademark of Bristol-Myers Squibb Company 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS). Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993. 2. National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993. Manufactured for: logo By: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Issued September 2008 Printed in USA 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) Tablets Read the Medication Guide that comes with NOROXIN before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN belongs to a class of antibiotics called fluoroquinolones. NOROXIN can cause side effects that may be serious or even cause death. If you get any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take NOROXIN. Tendon rupture or swelling of the tendon (tendinitis). • Tendons are tough cords of tissue that connect muscles to bones. • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone antibiotics, including NOROXIN. The risk of getting tendon problems is higher if you: o are over 60 years of age o are taking steroids (corticosteroids) o have had a kidney, heart or lung transplant • Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in patients who take fluoroquinolones who do not have the above risk factors. • Other reasons for tendon ruptures can include: o physical activity or exercise o kidney failure o tendon problems in the past, such as in people with rheumatoid arthritis (RA). • Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. • Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. • Get medical help right away if you get any of the following signs or symptoms of a tendon rupture: o hear or feel a snap or pop in a tendon area o bruising right after an injury in a tendon area o unable to move the affected area or bear weight • See the section “What are the possible side effects of NOROXIN?” for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone, joint, or tendon (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Who should not take NOROXIN? Do not take NOROXIN if you: • have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide. • have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you: • have tendon problems • have central nervous system problems (such as epilepsy) • have nerve problems • have myasthenia gravis • have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation” • have low blood potassium (hypokalemia) • have a slow heart beat (bradycardia) • have a history of seizures • have kidney problems. You may need a lower dose of NOROXIN if your kidneys do not work well. • have rheumatoid arthritis (RA) or other history of joint problems • are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child. • are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast- feed. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal and dietary supplements. NOROXIN and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: • an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?" • glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See "What are the possible side effects of NOROXIN?" • a blood thinner (warfarin, Coumadin, Jantoven) • a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?" • an anti-psychotic medicine • a tricyclic antidepressant • erythromycin • a water pill (diuretic) • a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. • probenecid (Probalan®, Col-probenecid®) • cyclosporine (Gengraf®, Sandimmune®, Neoral®) • products that contain caffeine • clozapine (Fazaclo ODT®, Clozaril®) • ropinirole (Requip®, Requip XL®) 14 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • tacrine (Cognex®) • tizanidine (Zanaflex®) • theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®) • cisapride (Propulsid®) • certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products: o an antacid, multivitamin, or other product that has iron or zinc o sucralfate (Carafate®) o didanosine (Videx®, Videx® EC) You should not take the medicine nitrofurantoin (furadantin, macrodantin, macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN? • Take NOROXIN exactly as prescribed by your healthcare provider. • NOROXIN is usually taken every 12 hours for patients with normal kidney function. • Take NOROXIN with a glass of water. • Drink plenty of fluids while taking NOROXIN. • Take NOROXIN at least 1 hour before or 2 hours after a meal or having milk or other dairy products. • Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless: o you have tendon effects (see “What is the most important information I should know about NOROXIN?”), o you have a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or o your healthcare provider tells you to stop. • This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future. • If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day. • If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN? NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you. Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include: 15 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Central Nervous System Effects: Seizures have been reported in people who take fluoroquinolone antibiotics including NOROXIN. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking NOROXIN will change your risk of having a seizure. Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of NOROXIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: o feel lightheaded o seizures o hear voices, see things, or sense things that are not there (hallucinations) o feel restless o tremors o feel anxious or nervous o confusion o feel more suspicious (paranoia) • Serious allergic reactions: Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: o hives o trouble breathing or swallowing o swelling of the lips, tongue, face o throat tightness, hoarseness o rapid heartbeat o faint o yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem). • Skin Rash: Skin rash may happen in people taking NOROXIN, even after only one dose. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN. • Serious heart rhythm changes (QT prolongation and torsades de pointes): Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: o who are elderly o with a family history of prolonged QT interval o with low blood potassium (hypokalemia), o who take certain medicines to control heart rhythm (antiarrhythmics). • Worsening of myasthenia gravis symptoms: Fluoroquinolones, including NOROXIN, may worsen the signs of myasthenia gravis. This may cause trouble breathing which may be life- threatening. Tell your healthcare provider if you get this symptom. • Intestine infection (Pseudomembranous colitis): Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. • Changes in sensation and possible nerve damage (Peripheral Neuropathy): Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including NOROXIN. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: o pain o burning o tingling 16 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda o numbness o weakness NOROXIN may need to be stopped to prevent permanent nerve damage. • Low blood sugar (hypoglycemia): People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed. • Sensitivity to sunlight (photosensitivity): See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include: • dizziness • nausea • diarrhea • heartburn • headache • stomach (abdominal) cramping • weakness • changes in certain liver function tests. These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store NOROXIN? • Store NOROXIN between 59 to 86°F (15-30°C). • Keep the container closed tightly. • Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? • Active ingredient: norfloxacin • Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide Revised: September 2008 Manufactured for: K MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 – Pavia, Italy 17 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda XXXXXXX This Medication Guide has been approved by the U.S. Food and Drug Administration. 18 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.597031	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019384s052lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 52}
11,488	NDA 19-384/S-054 Page 5 MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) 400 mg Tablets Read the Medication Guide that comes with NOROXIN before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN is an antibiotic called a fluoroquinolone. NOROXIN can cause side effects that may be serious or even cause death. If you develop any of the following serious side effects, get medical help right away, and talk with your healthcare provider about whether you should continue to take NOROXIN. Tendon rupture or swelling of the tendon (tendinitis). • Tendons are tough cords of tissue that connect muscle to bones. • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone antibiotics, including NOROXIN. The risk of getting tendon problems is higher if you: • are over 60 years of age • take steroids (corticosteroids) • have had a kidney, heart or lung transplant • Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in patients who take fluoroquinolones who do not have the above risk factors. • Other reasons for tendon ruptures can include: • physical activity or exercise • kidney failure • tendon problems in the past, such as in people with rheumatoid arthritis (RA). • Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that does not have a fluoroquinolone to treat your infection. • Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. • Get medical help right away if you have any of the following signs or symptoms of a tendon rupture: • hear or feel a snap or pop in a tendon area • bruising right after an incident in a tendon area • unable to move the affected area or bear weight • See the section "What are the possible side effects of NOROXIN?" for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone and joint (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-054 Page 6 See "What are the possible side effects of NOROXIN?' for more information about side effects. Who should not take NOROXIN? Do not take NOROXIN if you: • have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide. • have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you: • have tendon problems • have central nervous system problems (such as epilepsy) • have nerve problems • have myasthenia gravis • have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation.” • have low potassium (hypokalemia) • have a slow heartbeat called bradycardia • have a history of seizures • have kidney problems • have rheumatoid arthritis (RA) or other history of joint problems • are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child. • are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast-feed. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, herbal and dietary supplements. NOROXIN and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?" • glyburide(Micronase, Glynase, Diabeta, Glucovance). See "What are the possible side effects of NOROXIN?" • a blood thinner (warfarin, Coumadin, Jantoven) • a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?" • an anti-psychotic medicine • a tricyclic antidepressant • erythromycin • a water pill (diuretic) • a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. • probenecid (Probalan, Col-probenecid) • cyclosporine (Gengraf, Sandimmune, Neoral) • products that contain caffeine • clozapine (Fazaclo ODT, Clozaril) • ropinirole (Requip, Requip XL) • tacrine (Cognex) • tizanidine (Zanaflex) • theophylline (Theo-24, Elixophyllin, Theochron, Uniphyl, Theolair) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-054 Page 7 • cisapride (Propulsid) • certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products: • an antacid or multivitamin that contains iron or zinc • sulcrafate (Carafate) • didanosine (Videx®, Videx® EC) • You should not take the medicine nitrofuantoin (furadantin, macrodantin, macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if any of your medicines are the kind listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN? • Take NOROXIN exactly as prescribed by your healthcare provider. • NOROXIN is usually taken every 12 hours for patients with normal kidney function. • Take NOROXIN with a glass of water. • Drink plenty of fluids while taking NOROXIN. • Take NOROXIN at least one hour before or 2 hours after a meal or having milk or other dairy products. • Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless you have: • tendon effects (see “What is the most important information I should know about NOROXIN?”), • a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or • your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future. • If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day. • If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN? • NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you. • Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include: • Central Nervous System Effects. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking NOROXIN will change your risk of having a seizure. Seizures have been reported in patients taking fluoroquinolone antibiotics including NOROXIN. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-054 Page 8 Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of NOROXIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: • feel lightheaded • seizures • hear voices, see things, or sense things that are not there (hallucinations) • feel restless • tremors • feel anxious or nervous • confusion • feel more suspicious • Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: • hives • trouble breathing or swallowing • swelling of the lips, tongue, face • throat tightness, hoarseness • rapid heartbeat • faint • Skin rash. Skin rash may happen in people taking NOROXIN. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN. • Yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem). • Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are increased in people: • who are elderly • with a family history of prolonged QTc interval • with low blood potassium (hypokalemia) • who take certain drugs to control heart rhythm (antiarrhythmics) • Worsening of myasthenia gravis symptoms. Fluoroquinolones, including NOROXIN, may worsen the signs of myasthenia gravis. This may cause trouble breathing which may be life-threatening. Tell your healthcare provider right away if you get this symptom. • Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. • Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including NOROXIN. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: • pain • burning • tingling • numbness • weakness This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-054 Page 9 NOROXIN may need to be stopped to prevent permanent nerve damage. • Low blood sugar (hypoglycemia). People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include • dizziness • nausea • diarrhea • heartburn • headache • stomach (abdominal) cramping • weakness • changes in certain liver function tests These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088. How should I store NOROXIN? Store between 59-86°F (15-30°C). Keep container closed tightly. Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? Active ingredient: norfloxacin Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide Revised October 2008 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-054 Page 10 This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: K MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 – Pavia, Italy XXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.627887	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019384s054lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 54}
11,485	NDA 19-384/S-045 Page 3 TABLETS NOROXIN® (NORFLOXACIN) To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN† and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours † Registered trademark of MERCK & CO., Inc. COPYRIGHT © 1986, 1989, 1999, 2001. MERCK & CO., Inc. All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 4 of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) Microbiology Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid- susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 5 Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS.) Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the following criteria: MIC (µg/mL) Interpretation ≤4 Susceptible (S) 8 Intermediate (I) ≥16 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the following MIC values: Organism MIC range (µg/mL) E. coli ATCC 25922 0.03-0.12 E. faecalis ATCC 29212 2-8 P. aeruginosa ATCC 27853 1-4 S. aureus ATCC 29213 0.5-2 Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 6 test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the following criteria: Zone diameter (mm) Interpretation ≥17 Susceptible (S) 13-16 Intermediate (I) ≤12 Resistant (R) Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion techniques, the 10-µg norfloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Organism Zone Diameter (mm) E. coli ATCC 25922 28-35 P. aeruginosa ATCC 27853 22-29 S. aureus ATCC 25923 17-28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections: Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS): Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis: Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of * Efficacy for this organism in this organ system was studied in fewer than 10 infections. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 7 single doses of norfloxacin, 6 times* the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.) Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. (See ADVERSE REACTIONS.) Hypersensitivity/anaphylaxis: Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including norfloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic- associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Tendon effects: Ruptures of the shoulder, hand, Achilles tendons or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including norfloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Norfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including norfloxacin. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily * Based on a patient weight of 50 kg. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 8 recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe phototoxicity reactions have been observed in patients who are exposed to excessive sunlight while receiving some members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin. (See ADVERSE REACTIONS.) Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life-threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NOROXIN, in patients with myasthenia gravis (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour period before or within the two-hour period after taking norfloxacin. (See PRECAUTIONS, Drug Interactions.) — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — to avoid undue exposure to excessive sunlight while receiving norfloxacin and to discontinue therapy if phototoxicity occurs. — that some quinolones may increase the effects of theophylline and/or caffeine. (See PRECAUTIONS, Drug Interactions.) — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. ‡ Registered trademark of Bristol-Myers Squibb Company This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 9 Drug Interactions Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its plasma half-life. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well- controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 10 Geriatric Use Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 11 Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6- phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-384/S-045 Page 12 most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993. 2. National Committee for Clinical Laboratory Standards, Performance standards for antimicrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993. Manufactured for: By: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Issued September 2005 Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:22.740348	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019384s045lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 45}
11,491	TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN® and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 μg/g Prostate 2.5 μg/g Seminal Fluid 2.7 μg/mL Testicle 1.6 μg/g Uterus/Cervix 3.0 μg/g Vagina 4.3 μg/g Fallopian Tube 1.9 μg/g Bile 6.9 μg/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; 2 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method{1} (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. 3 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure{2} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for Norfloxacin MIC (μg/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-μg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (μg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii1, Enterobacter aerogenes1, Enterobacter cloacae1, Proteus vulgaris1, Staphylococcus aureus1, or Streptococcus agalactiae1. 1 Efficacy for this organism in this organ system was studied in fewer than 10 infections. 4 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens1. Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post- marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral 5 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of single doses of norfloxacin, 6 times2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Central Nervous System Effects/Disorders: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium Difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been 2 Based on a patient weight of 50 kg. 6 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Syphilis Treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. 7 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda — that multivitamins or other products containing iron or zinc, antacids or Videx®3 (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two- hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. 3 Registered trademark of Bristol-Myers Squibb Company 8 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and 9 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). 10 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis. Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: 11 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. 12 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 11/2011 9900807 13 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) Tablets Read the Medication Guide that comes with NOROXIN® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN belongs to a class of antibiotics called fluoroquinolones. NOROXIN can cause side effects that may be serious or even cause death. If you develop any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take NOROXIN. 1. Tendon rupture or swelling of the tendon (tendinitis) • Tendon problems can happen in people of all ages who take NOROXIN. Tendons are tough cords of tissue that connect muscle to bones. Symptoms of tendon problems may include: • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. • The risk of getting tendon problems while you take NOROXIN is higher if you: • are over 60 years of age • are taking steroids (corticosteroids) • have had a kidney, heart or lung transplant • Tendon problems can happen in people who do not have the above risk factors when they take NOROXIN. Other reasons that can increase your risk of tendon problems can include: • physical activity or exercise • kidney failure • tendon problems in the past, such as in people with rheumatoid arthritis (RA) • Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. • Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. • Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. • Get medical help right away if you get any of the following signs or symptoms of a tendon rupture: • hear or feel a snap or pop in a tendon area • bruising right after an incident in a tendon area • unable to move the affected area or bear weight Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Worsening of myasthenia gravis (a disease which causes muscle weakness) Fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. See the section "What are the possible side effects of NOROXIN?" for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone and joint (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. Who should not take NOROXIN? Do not take NOROXIN if you: • have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide. • have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you: • have tendon problems • have a disease that causes muscle weakness (myasthenia gravis) • have central nervous system problems (such as epilepsy) • have nerve problems • have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation” • have low potassium (hypokalemia) • have a slow heartbeat called bradycardia • have a history of seizures • have kidney problems. You may need a lower dose of NOROXIN if your kidneys do not work well. • have rheumatoid arthritis (RA) or other history of joint problems • are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child. • are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast-feed. 2 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal and dietary supplements. NOROXIN and other medicines1 can affect each other causing side effects. Especially tell your healthcare provider if you take: • an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?" • glyburide (Micronase, Glynase, Diabeta, Glucovance). See "What are the possible side effects of NOROXIN?" • a blood thinner (warfarin, Coumadin, Jantoven) • a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?" • an anti-psychotic medicine • a tricyclic antidepressant • erythromycin • a water pill (diuretic) • a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. • probenecid (Probalan, Col-probenecid) • cyclosporine (Gengraf, Sandimmune, Neoral) • products that contain caffeine • clozapine (Fazaclo ODT, Clozaril) • ropinirole (Requip, Requip XL) • tacrine (Cognex) • tizanidine (Zanaflex) • theophylline (Theo-24, Elixophyllin, Theochron, Uniphyl, Theolair) • cisapride (Propulsid) • certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products: • an antacid, multivitamin or other product that has iron or zinc • sucralfate (Carafate) • didanosine (Videx, Videx EC) • You should not take the medicine nitrofurantoin (Furadantin, Macrodantin, Macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN? • Take NOROXIN exactly as prescribed by your healthcare provider. • NOROXIN is usually taken every 12 hours for patients with normal kidney function. • Take NOROXIN with a glass of water. • Drink plenty of fluids while taking NOROXIN. • Take NOROXIN at least one hour before or 2 hours after a meal or having milk or other dairy products. 1 Other brands listed are the trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp. 3 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless: • you have tendon effects (see “What is the most important information I should know about NOROXIN?”), • you have a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or • your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future. • If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day. • If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN? • NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you. • Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include: • Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including NOROXIN. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking NOROXIN will change your risk of having a seizure. Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of NOROXIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: • feel lightheaded • seizures • hear voices, see things, or sense things that are not there (hallucinations) • feel restless • tremors • feel anxious or nervous • confusion • feel more suspicious (paranoia) • Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: • hives • trouble breathing or swallowing • swelling of the lips, tongue, face • throat tightness, hoarseness 4 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • rapid heartbeat • faint • yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem). • Skin rash. Skin rash may happen in people taking NOROXIN, even after only one dose. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN. • Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: • who are elderly • with a family history of prolonged QTc interval • with low blood potassium (hypokalemia) • who take certain medicines to control heart rhythm (antiarrhythmics) • Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. • Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including NOROXIN. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: • pain • burning • tingling • numbness • weakness NOROXIN may need to be stopped to prevent permanent nerve damage. • Low blood sugar (hypoglycemia). People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include: • dizziness • nausea • diarrhea • heartburn • headache • stomach (abdominal) cramping • weakness • changes in certain liver function tests 5 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NOROXIN? Store between 59-86°F (15-30°C). Keep container closed tightly. Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? Active ingredient: norfloxacin Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 11/2011 9900807 6 Reference ID: 3084077 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.012072	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019384s062lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 62}
11,490	Company logo XXXXXXX TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN* and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. * Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved Reference ID: 3015995 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 μg/g Prostate 2.5 μg/g Seminal Fluid 2.7 μg/mL Testicle 1.6 μg/g Uterus/Cervix 3.0 μg/g Vagina 4.3 μg/g Fallopian Tube 1.9 μg/g Bile 6.9 μg/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Reference ID: 3015995 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or Reference ID: 3015995 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for norfloxacin MIC (μg/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-μg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (μg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Efficacy for this organism in this organ system was studied in fewer than 10 infections. Reference ID: 3015995 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of myasthenia gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post- marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a * Based on a patient weight of 50 kg. Reference ID: 3015995 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium difficile associated diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Reference ID: 3015995 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two ‡ Registered trademark of Bristol-Myers Squibb Company Reference ID: 3015995 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Reference ID: 3015995 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). Reference ID: 3015995 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS). Reference ID: 3015995 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Reference ID: 3015995 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. Reference ID: 3015995 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. company logo By: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Issued Month Year Printed in USA 13 Reference ID: 3015995 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.118260	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019384s061lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 61}
11,492	TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN® and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 g/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) ghr/mL and 2.02 (0.77) g/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda higher than that seen in younger adults (AUC 6.4 ghr/mL and Cmax 1.5 g/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 g of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 g/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 g/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 g/g Prostate 2.5 g/g Seminal Fluid 2.7 g/mL Testicle 1.6 g/g Uterus/Cervix 3.0 g/g Vagina 4.3 g/g Fallopian Tube 1.9 g/g Bile 6.9 g/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; 2 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of 4 g/mL against most (90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method{1} (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. 3 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure{2} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-g norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-g norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for Norfloxacin MIC (g/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-g norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (g/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii1, Enterobacter aerogenes1, Enterobacter cloacae1, Proteus vulgaris1, Staphylococcus aureus1, or Streptococcus agalactiae1. 1 Efficacy for this organism in this organ system was studied in fewer than 10 infections. Reference ID: 3146487 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens1. Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post- marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral 5 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda administration of single doses of norfloxacin, 6 times2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Central Nervous System Effects/Disorders: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:  fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);  vasculitis; arthralgia; myalgia; serum sickness;  allergic pneumonitis;  interstitial nephritis; acute renal insufficiency or failure;  hepatitis; jaundice; acute hepatic necrosis or failure;  anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium Difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been 2 Based on a patient weight of 50 kg. 6 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Syphilis Treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. 7 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda — that multivitamins or other products containing iron or zinc, antacids or Videx®3 (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two- hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. 3 Registered trademark of Bristol-Myers Squibb Company 8 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and 9 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). 10 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: 11 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg)  (140 – age) (72)  serum creatinine (mg/100 mL) Females: (0.85)  (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. 12 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 06/2012 13 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) Tablets Read the Medication Guide that comes with NOROXIN® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN belongs to a class of antibiotics called fluoroquinolones. NOROXIN can cause side effects that may be serious or even cause death. If you develop any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take NOROXIN. 1. Tendon rupture or swelling of the tendon (tendinitis)  Tendon problems can happen in people of all ages who take NOROXIN. Tendons are tough cords of tissue that connect muscle to bones. Symptoms of tendon problems may include:  Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.  The risk of getting tendon problems while you take NOROXIN is higher if you:  are over 60 years of age  are taking steroids (corticosteroids)  have had a kidney, heart or lung transplant  Tendon problems can happen in people who do not have the above risk factors when they take NOROXIN. Other reasons that can increase your risk of tendon problems can include:  physical activity or exercise  kidney failure  tendon problems in the past, such as in people with rheumatoid arthritis (RA)  Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons.  Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.  Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone.  Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:  hear or feel a snap or pop in a tendon area  bruising right after an incident in a tendon area  unable to move the affected area or bear weight Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Worsening of myasthenia gravis (a disease which causes muscle weakness) Fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. See the section "What are the possible side effects of NOROXIN?" for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone and joint (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. Who should not take NOROXIN? Do not take NOROXIN if you:  have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide.  have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you:  have tendon problems  have a disease that causes muscle weakness (myasthenia gravis)  have central nervous system problems (such as epilepsy)  have nerve problems  have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation”  have low potassium (hypokalemia)  have a slow heartbeat called bradycardia  have a history of seizures  have kidney problems. You may need a lower dose of NOROXIN if your kidneys do not work well.  have rheumatoid arthritis (RA) or other history of joint problems  are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child.  are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast-feed. 2 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal and dietary supplements. NOROXIN and other medicines1 can affect each other causing side effects. Especially tell your healthcare provider if you take:  an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?"  glyburide (Micronase, Glynase, Diabeta, Glucovance). See "What are the possible side effects of NOROXIN?"  a blood thinner (warfarin, Coumadin, Jantoven)  a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?"  an anti-psychotic medicine  a tricyclic antidepressant  erythromycin  a water pill (diuretic)  a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury.  probenecid (Probalan, Col-probenecid)  cyclosporine (Gengraf, Sandimmune, Neoral)  products that contain caffeine  clozapine (Fazaclo ODT, Clozaril)  ropinirole (Requip, Requip XL)  tacrine (Cognex)  tizanidine (Zanaflex)  theophylline (Theo-24, Elixophyllin, Theochron, Uniphyl, Theolair)  cisapride (Propulsid)  certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products:  an antacid, multivitamin or other product that has iron or zinc  sucralfate (Carafate)  didanosine (Videx, Videx EC)  You should not take the medicine nitrofurantoin (Furadantin, Macrodantin, Macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN?  Take NOROXIN exactly as prescribed by your healthcare provider.  NOROXIN is usually taken every 12 hours for patients with normal kidney function.  Take NOROXIN with a glass of water.  Drink plenty of fluids while taking NOROXIN.  Take NOROXIN at least one hour before or 2 hours after a meal or having milk or other dairy products. 1 Other brands listed are the trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp. 3 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless:  you have tendon effects (see “What is the most important information I should know about NOROXIN?”),  you have a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or  your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future.  If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day.  If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN?  NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you.  Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include:  Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including NOROXIN. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking NOROXIN will change your risk of having a seizure. Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of NOROXIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:  feel lightheaded  seizures  hear voices, see things, or sense things that are not there (hallucinations)  feel restless  tremors  feel anxious or nervous  confusion  feel more suspicious (paranoia)  Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:  hives  trouble breathing or swallowing  swelling of the lips, tongue, face  throat tightness, hoarseness 4 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  rapid heartbeat  faint  skin rash accompanied by fever and feeling unwell  yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem).  Skin rash. Skin rash may happen in people taking NOROXIN, even after only one dose. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN.  Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:  who are elderly  with a family history of prolonged QTc interval  with low blood potassium (hypokalemia)  who take certain medicines to control heart rhythm (antiarrhythmics)  Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.  Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including NOROXIN. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:  pain  burning  tingling  numbness  weakness NOROXIN may need to be stopped to prevent permanent nerve damage.  Low blood sugar (hypoglycemia). People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed.  Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include:  dizziness  nausea  diarrhea  heartburn  headache  stomach (abdominal) cramping 5 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  weakness  changes in certain liver function tests These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NOROXIN? Store between 59-86F (15-30C). Keep container closed tightly. Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? Active ingredient: norfloxacin Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide This Medication Guide has been approved by the U.S. Food and Drug Administration. company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 06/2012 6 Reference ID: 3146487 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.127352	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019384s063lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 63}
11,493	TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN® and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method{1} (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure{2} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for Norfloxacin MIC (µg/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-µg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (µg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii1, Enterobacter aerogenes1, Enterobacter cloacae1, Proteus vulgaris1, Staphylococcus aureus1, or Streptococcus agalactiae1. 1 Efficacy for this organism in this organ system was studied in fewer than 10 infections. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens1. Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post- marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these 2 Based on a patient weight of 50 kg. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Central Nervous System Effects/Disorders: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium Difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 Syphilis Treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6- phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx ®3 (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour 3 Registered trademark of Bristol-Myers Squibb Company Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 9 Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 11 Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK), muscle spasms. Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6- phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 12/2012 USPI-T-03661212R010 Reference ID: 3283710 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.449489	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019384s065lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 65}
11,489	company logo XXXXXXX TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN* and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3 quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. * Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved Reference ID: 3030784 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 μg/g Prostate 2.5 μg/g Seminal Fluid 2.7 μg/mL Testicle 1.6 μg/g Uterus/Cervix 3.0 μg/g Vagina 4.3 μg/g Fallopian Tube 1.9 μg/g Bile 6.9 μg/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Reference ID: 3030784 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 μg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth, agar, or Reference ID: 3030784 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-μg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-μg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for norfloxacin MIC (μg/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-μg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (μg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae. Efficacy for this organism in this organ system was studied in fewer than 10 infections. Reference ID: 3030784 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens. Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of myasthenia gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post- marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times* the recommended human clinical dose (on a * Based on a patient weight of 50 kg. Reference ID: 3030784 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Central nervous system effects/disorders: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium difficile associated diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including norfloxacin. Norfloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or Reference ID: 3030784 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition. Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. While crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Reference ID: 3030784 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX — that multivitamins or other products containing iron or zinc, antacids or Videx®‡ (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two- hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. ‡ Registered trademark of Bristol-Myers Squibb Company Reference ID: 3030784 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times* the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times* the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times* the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times* the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times*** the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See WARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed Warning; WARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and Reference ID: 3030784 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Reference ID: 3030784 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS). Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK). Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Reference ID: 3030784 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-68 bottles of 100 NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. Reference ID: 3030784 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN® (Norfloxacin) XXXXXXX REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. company logo By: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Issued Month Year Printed in USA 13 Reference ID: 3030784 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.694534	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019384s060lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 60}
11,494	TABLETS NOROXIN® (NORFLOXACIN) WARNING: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS). Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN® and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6 fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). W ithin 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) 2 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid- resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae 3 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see WARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method{1} (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure{2} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for Norfloxacin MIC (µg/mL) Zone Diameter (mm) S I R S I R 4 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant of "Susceptible" indicates that t he pathogen is likely to be inhibited if t he antimicrobial compound in the blood reaches the A report concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-µg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (µg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii1, Enterobacter aerogenes1, Enterobacter cloacae1, Proteus vulgaris1, Staphylococcus aureus1, or Streptococcus agalactiae1. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens1. 1 Efficacy for this organism in this organ system was studied in fewer than 10 infections. 5 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Sexually transmitted diseases (see WARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. W hen culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Tendinopathy and Tendon Rupture: Fluoroquinolones, including NOROXIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. NOROXIN should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses 6 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of norfloxacin, 6 times 2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Central Nervous System Effects/Disorders: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Clostridium Difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 2 Based on a patient weight of 50 kg. 7 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Merck accepts the requested revisions under “Information for Peripheral Neuropathy: Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including norfloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible. Norfloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation.. Syphilis Treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. W hile crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised: — to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. 8 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — that peripheral neuropathies have been associated with norfloxacin use,that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue norfloxacin and contact their physicians. — to drink fluids liberally. — that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®3 (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that norfloxacin can cause dizziness and lightheadedness and, therefore, patients should know how they react to norfloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. — that norfloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction. — that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition. — that diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). W hen NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. 3 Registered trademark of Bristol-Myers Squibb Company 9 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. W hen these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. 10 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda W hen a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See W ARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed W arning; W ARNINGS; and ADVERSE REACTIONS, Post- Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see W ARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug- related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased W BC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). 11 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased W BC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see W ARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see W ARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see W ARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy that may be irreversible, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see WARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK), muscle spasms. 12 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6-phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. uveitis Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg 13 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. W hen only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see WARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. 14 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 07/2013 USPI-T-03661212R010 15 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) Tablets Read the Medication Guide that comes with NOROXIN® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN belongs to a class of antibiotics called fluoroquinolones. NOROXIN can cause side effects that may be serious or even cause death. If you develop any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take NOROXIN. 1. Tendon rupture or swelling of the tendon (tendinitis) • Tendon problems can happen in people of all ages who take NOROXIN. Tendons are tough cords of tissue that connect muscle to bones. Symptoms of tendon problems may include: • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. • The risk of getting tendon problems while you take NOROXIN is higher if you: • are over 60 years of age • are taking steroids (corticosteroids) • have had a kidney, heart or lung transplant • Tendon problems can happen in people who do not have the above risk factors when they take NOROXIN. Other reasons that can increase your risk of tendon problems can include: • physical activity or exercise • kidney failure • tendon problems in the past, such as in people with rheumatoid arthritis (RA) • Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. • Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. • Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. • Get medical help right away if you get any of the following signs or symptoms of a tendon rupture: • hear or feel a snap or pop in a tendon area • bruising right after an incident in a tendon area • unable to move the affected area or bear weight Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Worsening of myasthenia gravis (a disease which causes muscle weakness) Fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. See the section "What are the possible side effects of NOROXIN?" for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone and joint (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. Who should not take NOROXIN? Do not take NOROXIN if you: • have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide. • have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you: • have tendon problems • have a disease that causes muscle weakness (myasthenia gravis) • have central nervous system problems (such as epilepsy) • have nerve problems • have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation” • have low potassium (hypokalemia) • have a slow heartbeat called bradycardia • have a history of seizures • have kidney problems. You may need a lower dose of NOROXIN if your kidneys do not work well. • have rheumatoid arthritis (RA) or other history of joint problems • are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child. • are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast-feed. 2 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal and dietary supplements. NOROXIN and other medicines 1 can affect each other causing side effects. Especially tell your healthcare provider if you take: • an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?" • glyburide (Micronase, Glynase, Diabeta, Glucovance). See "What are the possible side effects of NOROXIN?" • a blood thinner (warfarin, Coumadin, Jantoven) • a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?" • an anti-psychotic medicine • a tricyclic antidepressant • erythromycin • a water pill (diuretic) • a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. • probenecid (Probalan, Col-probenecid) • cyclosporine (Gengraf, Sandimmune, Neoral) • products that contain caffeine • clozapine (Fazaclo ODT, Clozaril) • ropinirole (Requip, Requip XL) • tacrine (Cognex) • tizanidine (Zanaflex) • theophylline (Theo-24, Elixophyllin, Theochron, Uniphyl, Theolair) • cisapride (Propulsid) • certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products: • an antacid, multivitamin or other product that has iron or zinc • sucralfate (Carafate) • didanosine (Videx, Videx EC) • You should not take the medicine nitrofurantoin (Furadantin, Macrodantin, Macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN? • Take NOROXIN exactly as prescribed by your healthcare provider. • NOROXIN is usually taken every 12 hours for patients with normal kidney function. • Take NOROXIN with a glass of water. • Drink plenty of fluids while taking NOROXIN. • Take NOROXIN at least one hour before or 2 hours after a meal or having milk or other dairy products. 1 Other brands listed are the trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp. 3 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless: • you have tendon effects (see “What is the most important information I should know about NOROXIN?”), • you have a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or • your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future. • If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day. • If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN? • NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you. • Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include: • Central Nervous System Effects. Seizures have been reported in people who take fluoroquinolone antibiotics including NOROXIN. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking NOROXIN will change your risk of having a seizure. Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of NOROXIN. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: • feel lightheaded • seizures • hear voices, see things, or sense things that are not there (hallucinations) • feel restless • tremors • feel anxious or nervous • confusion • feel more suspicious (paranoia) • Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: • hives • trouble breathing or swallowing • swelling of the lips, tongue, face • throat tightness, hoarseness 4 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • rapid heartbeat • faint • skin rash accompanied by fever and feeling unwell • yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem). • Skin rash. Skin rash may happen in people taking NOROXIN, even after only one dose. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN. • Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: • who are elderly • with a family history of prolonged QTc interval • with low blood potassium (hypokalemia) • who take certain medicines to control heart rhythm (antiarrhythmics) • Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. • Changes in sensation and nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including NOROXIN. Stop NOROXIN and talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: • pain • burning • tingling • numbness • weakness The nerve damage may be permanent. • Low blood sugar (hypoglycemia). People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include: • dizziness • nausea • diarrhea • heartburn • headache • stomach (abdominal) cramping • weakness 5 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda c o m p any logo • changes in certain liver function tests These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NOROXIN? Store between 59-86°F (15-30°C). Keep container closed tightly. Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? Active ingredient: norfloxacin Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide This Medication Guide has been approved by the U.S. Food and Drug Administration. Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 07/2013 USMG-T-03661307RXXX 6 Reference ID: 3356550 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.696019	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019384s066lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 66}
11,495	TABLETS NOROXIN® (NORFLOXACIN) WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS • Fluoroquinolones, including NOROXIN, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including: • Tendinitis and tendon rupture • Peripheral neuropathy • Central nervous system effects (see WARNINGS). Discontinue NOROXIN immediately and avoid the use of fluoroquinolones, including NOROXIN, in patients who experience any of these serious adverse reactions. • Fluoroquinolones, including NOROXIN, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis (see WARNINGS). • Because fluoroquinolones, including NOROXIN, have been associated with serious adverse reactions (see WARNINGS), reserve NOROXIN for use in patients who have no alternative treatment options for uncomplicated urinary tract infections (including cystitis) (see INDICATIONS and USAGE). To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN® and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NOROXIN (Norfloxacin) is a synthetic, broad-spectrum antibacterial agent for oral administration. Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is: structural formula Norfloxacin is a white to pale yellow crystalline powder with a molecular weight of 319.34 and a melting point of about 221°C. It is freely soluble in glacial acetic acid, and very slightly soluble in ethanol, methanol and water. NOROXIN is available in 400-mg tablets. Each tablet contains the following inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, and titanium dioxide. Norfloxacin, a fluoroquinolone, differs from non-fluorinated quinolones by having a fluorine atom at the 6 position and a piperazine moiety at the 7 position. Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CLINICAL PHARMACOLOGY In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 µg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing. In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg•hr/mL and 2.02 (0.77) µg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg•hr/mL and Cmax 1.5 µg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours. There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment). The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary (see DOSAGE AND ADMINISTRATION). Drug absorption appears unaffected by decreasing renal function. Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 µg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). W ithin 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min. Two to three hours after a single 400-mg dose, urinary concentrations of 200 µg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 µg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%. The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated: Renal Parenchyma 7.3 µg/g Prostate 2.5 µg/g Seminal Fluid 2.7 µg/mL Testicle 1.6 µg/g Uterus/Cervix 3.0 µg/g Vagina 4.3 µg/g Fallopian Tube 1.9 µg/g Bile 6.9 µg/mL (after two 200-mg doses) Microbiology Mechanism of Action Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells: 1) inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, 2) inhibition of the relaxation of supercoiled DNA, 3) promotion of double-stranded DNA breakage. 2 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity. Drug Resistance Resistance to norfloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to 10-12 cells). Resistant organisms have emerged during therapy with norfloxacin in less than 1% of patients treated. Organisms in which development of resistance is greatest are the following: Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter spp. Enterococcus spp. For this reason, when there is a lack of satisfactory clinical response, repeat culture and susceptibility testing should be done. Nalidixic acid-resistant organisms are generally susceptible to norfloxacin in vitro; however, these organisms may have higher minimum inhibitory concentrations (MICs) to norfloxacin than nalidixic acid-susceptible strains. There is generally no cross-resistance between norfloxacin and other classes of antibacterial agents. Therefore, norfloxacin may demonstrate activity against indicated organisms resistant to some other antimicrobial agents including the aminoglycosides, penicillins, cephalosporins, tetracyclines, macrolides, and sulfonamides, including combinations of sulfamethoxazole and trimethoprim. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin. Activity in vitro and in vivo Norfloxacin has in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria. Norfloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus agalactiae Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is unknown. Norfloxacin exhibits in vitro MICs of ≤4 µg/mL against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of norfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-negative aerobes: Citrobacter diversus Edwardsiella tarda Enterobacter agglomerans Haemophilus ducreyi Klebsiella oxytoca Morganella morganii Providencia alcalifaciens Providencia rettgeri Providencia stuartii Pseudomonas fluorescens Pseudomonas stutzeri 3 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Other: Ureaplasma urealyticum NOROXIN is not generally active against obligate anaerobes. Norfloxacin has not been shown to be active against Treponema pallidum (see W ARNINGS). Susceptibility Tests Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method{1} (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of norfloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure{2} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg norfloxacin to test the susceptibility of microorganisms to norfloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg norfloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for norfloxacin. Table 1: Susceptibility Interpretive Criteria for Norfloxacin MIC (µg/mL) Zone Diameter (mm) S I R S I R ≤4 8 ≥16 ≥17 13-16 ≤12 These interpretative criteria apply only to isolates from urinary tract infections. There are no established norfloxacin interpretive criteria for Neisseria gonorrhoeae or organisms isolated from other infection sites. S=Susceptible, I=Intermediate, and R=Resistant A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard norfloxacin powder should provide the MIC values outlined in Table 2. For the diffusion techniques, the 10-µg norfloxacin disk should provide the zone diameters outlined in Table 2. Table 2: Quality Control for Susceptibility Testing Strains MIC Range (µg/mL) Zone Diameter (mm) Enterococcus faecalis (ATCC 29212) 2 – 8 Not applicable Escherichia coli (ATCC 25922) 0.03 – 0.12 28 – 35 P. aeruginosa (ATCC 27853) 1 – 4 22 – 29 Staphylococcus aureus (ATCC 29213) 0.5 – 2 Not applicable Staphylococcus aureus (ATCC 25923) Not applicable 17 – 28 4 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INDICATIONS AND USAGE NOROXIN is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms: Urinary tract infections Uncomplicated urinary tract infections (including cystitis) due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii1, Enterobacter aerogenes1, Enterobacter cloacae1, Proteus vulgaris1, Staphylococcus aureus1, or Streptococcus agalactiae1. Because fluoroquinolones, including NOROXIN, have been associated with serious adverse reactions (see W ARNINGS), and for some patients uncomplicated urinary tract infection is self-limiting, reserve NOROXIN for treatment of uncomplicated urinary tract infections (including cystitis) in patients who have no alternative treatment options. Complicated urinary tract infections due to Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Serratia marcescens1. Sexually transmitted diseases (see W ARNINGS) Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Prostatitis Prostatitis due to Escherichia coli. (See DOSAGE AND ADMINISTRATION for appropriate dosing instructions.) Penicillinase production should have no effect on norfloxacin activity. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to norfloxacin. Therapy with norfloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be given. Repeat culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agents but also on the possible emergence of bacterial resistance. To reduce the development of drug-resistant bacteria and maintain the effectiveness of NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NOROXIN (norfloxacin) is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents. WARNINGS Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects: Fluoroquinolones, including NOROXIN, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly s een adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting NOROXIN. Patients of any age or without pre-existing risk factors have experienced these adverse reactions (see W ARNINGS, Tendinitis and Tendon Rupture, Peripheral Neuropathy and Central Nervous System Effects). Discontinue NOROXIN immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including NOROXIN, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 1 Efficacy for this organism in this organ system was studied in fewer than 10 infections. 5 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tendinitis and Tendon Rupture: Fluoroquinolones, including NOROXIN, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting NOROXIN, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue NOROXIN immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including NOROXIN, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture (see ADVERSE REACTIONS). Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Peripheral Neuropathy: Fluoroquinolones, including NOROXIN, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including NOROXIN. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients (see W ARNINGS). Discontinue NOROXIN immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including NOROXIN, in patients who have previously experienced peripheral neuropathy (see ADVERSE REACTIONS). Central Nervous System Effects: Fluoroquinolones, including NOROXIN, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses. Quinolones may also cause CNS stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures (see ADVERSE REACTIONS). Exacerbation of Myasthenia Gravis: Fluoroquinolones, including NOROXIN, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid NOROXIN in patients with known history of myasthenia gravis. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS, Post-Marketing, Musculoskeletal.) Safety in Children, Adolescents, Nursing mothers, and during Pregnancy: THE SAFETY AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of norfloxacin, 6 times 2 the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species (see ANIMAL PHARMACOLOGY). Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including 2 Based on a patient weight of 50 kg. 6 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOROXIN. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); • vasculitis; arthralgia; myalgia; serum sickness; • allergic pneumonitis; • interstitial nephritis; acute renal insufficiency or failure; • hepatitis; jaundice; acute hepatic necrosis or failure; • anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS). Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including NOROXIN. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated. Clostridium Difficile Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including NOROXIN and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Syphilis Treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months. PRECAUTIONS General Needle-shaped crystals were found in the urine of some volunteers who received either placebo, 800 mg norfloxacin, or 1600 mg norfloxacin (at or twice the recommended daily dose, respectively) while participating in a double-blind, crossover study comparing single doses of norfloxacin with placebo. W hile crystalluria is not expected to occur under usual conditions with a dosage regimen of 400 mg b.i.d., as a precaution, the daily recommended dosage should not be exceeded and the patient should drink sufficient fluids to ensure a proper state of hydration and adequate urinary output. Alteration in dosage regimen is necessary for patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. 7 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS, Post-Marketing). Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6 phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see ADVERSE REACTIONS). Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Serious Adverse Reactions Advise patients to stop taking NOROXIN if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug. Inform patients of the following serious adverse reactions that have been associated with NOROXIN or other fluoroquinolone use: — Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of NOROXIN and may occur together in the same patient. Inform patients to stop taking NOROXIN immediately if they experience an adverse reaction and to call their healthcare provider. — Tendinitis and Tendon Rupture: instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue NOROXIN treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. — Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with the use of NOROXIN, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should immediately discontinue NOROXIN and contact their physicians. — Central Nervous System Effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including NOROXIN. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to norfloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs. — Exacerbation of Myasthenia Gravis: inform patients that fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. — Hypersensitivity Reactions: Inform patients that NOROXIN can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction. — Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking NOROXIN. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine. — Diarrhea: Inform patients that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more 8 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible. — Prolongation of the QT interval: inform patients of the following: — that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation). — that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents. — that norfloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. — to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia. — Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician. Other Information Patients should be advised: — to drink fluids liberally. — that NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. — that multivitamins or other products containing iron or zinc, antacids or Videx®3 (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour period before or within the two-hour period after taking norfloxacin (see PRECAUTIONS, Drug Interactions). — that some quinolones may increase the effects of theophylline and/or caffeine (see PRECAUTIONS, Drug Interactions). — that convulsions have been reported in patients taking quinolones, including NOROXIN, and to notify their physician before taking this drug if there is a history of this condition. Patients should be counseled that antibacterial drugs including NOROXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). W hen NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future. Laboratory Tests As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. Drug Interactions Quinolones, including NOROXIN, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored. Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required. Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with NOROXIN. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly. 3 Registered trademark of Bristol-Myers Squibb Company 9 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Quinolones, including NOROXIN, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. W hen these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. The concomitant administration of quinolones including NOROXIN with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered. Diminished urinary excretion of NOROXIN has been reported during the concomitant administration of probenecid and NOROXIN. The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract. Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of NOROXIN, because they may interfere with absorption resulting in lower serum and urine levels of NOROXIN. Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of NOROXIN, because these products may interfere with absorption resulting in lower serum and urine levels of NOROXIN. Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking NOROXIN. The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including NOROXIN, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility No increase in neoplastic changes was observed with norfloxacin as compared to controls in a study in rats, lasting up to 96 weeks at doses 8-9 times2 the usual human dose (on a mg/kg basis). Norfloxacin was tested for mutagenic activity in a number of in vivo and in vitro tests. Norfloxacin had no mutagenic effect in the dominant lethal test in mice and did not cause chromosomal aberrations in hamsters or rats at doses 30-60 times2 the usual human dose (on a mg/kg basis). Norfloxacin had no mutagenic activity in vitro in the Ames microbial mutagen test, Chinese hamster fibroblasts and V-79 mammalian cell assay. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, all other mutagenic assays were negative including a more sensitive test (V-79). Norfloxacin did not adversely affect the fertility of male and female mice at oral doses up to 30 times2 the usual human dose (on a mg/kg basis). Pregnancy Teratogenic Effects. Pregnancy Category C. Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether norfloxacin is excreted in human milk. W hen a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species. (See W ARNINGS and ANIMAL PHARMACOLOGY.) Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as NOROXIN. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, 10 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing NOROXIN to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue NOROXIN and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (see Boxed W arning; W ARNINGS; and ADVERSE REACTIONS, Post-Marketing). Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMACOLOGY). In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using NOROXIN concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia). ADVERSE REACTIONS Single-Dose Studies In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%). Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting. Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased W BC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%). Multiple-Dose Studies In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship. The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%). Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting. Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria. Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased W BC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria. Post-Marketing The most frequently reported adverse reaction in post-marketing experience is rash. 11 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see W ARNINGS). Visual disturbances have been reported with drugs in this class. The following additional adverse reactions have been reported since the drug was marketed: Hypersensitivity Reactions Hypersensitivity reactions have been reported including anaphylactoid reactions, angioedema, dyspnea, vasculitis, urticaria, arthritis, arthralgia and myalgia (see WARNINGS). Skin Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme, exfoliative dermatitis, photosensitivity/phototoxicity reactions (see PRECAUTIONS), leukocytoclastic vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Gastrointestinal Pseudomembranous colitis, hepatitis, jaundice including cholestatic jaundice and elevated liver function tests, pancreatitis (rare), stomatitis. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see W ARNINGS). Hepatic Hepatic failure, including fatal cases. Cardiovascular On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes. Renal Interstitial nephritis, renal failure. Nervous System/Psychiatric Peripheral neuropathy that may be irreversible, Guillain-Barré syndrome, ataxia, paresthesia, hypoesthesia, psychic disturbances including psychotic reactions and confusion. Musculoskeletal Tendinitis, tendon rupture; exacerbation of myasthenia gravis (see W ARNINGS, Exacerbation of myasthenia gravis); elevated creatine kinase (CK), muscle spasms. Hematologic Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6 phosphate dehydrogenase deficiency; thrombocytopenia. Special Senses Hearing loss, tinnitus, diplopia, dysgeusia. Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis. OVERDOSAGE No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained. DOSAGE AND ADMINISTRATION Tablets NOROXIN should be taken at least one hour before or at least two hours after a meal or ingestion of milk and/or other dairy products. Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx ® (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin. Tablets NOROXIN should be taken with a glass of water. Patients receiving NOROXIN should be well hydrated (see PRECAUTIONS). Normal Renal Function The recommended daily dose of NOROXIN is as described in the following chart: 12 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Infection Description Unit Dose Frequency Duration Daily Dose Urinary Tract Uncomplicated UTI's (cystitis) due to E. coli, K. pneumoniae, or P. mirabilis 400 mg q12h 3 days 800 mg Uncomplicated UTI's due to other indicated organisms 400 mg q12h 7-10 days 800 mg Complicated UTI's 400 mg q12h 10-21 days 800 mg Sexually Transmitted Diseases Uncomplicated Gonorrhea 800 mg single dose 1 day 800 mg Prostatitis Acute or Chronic 400 mg q12h 28 days 800 mg Renal Impairment NOROXIN may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2. W hen only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: (weight in kg) × (140 – age) (72) × serum creatinine (mg/100 mL) Females: (0.85) × (above value) Elderly Elderly patients being treated for urinary tract infections who have a creatinine clearance of greater than 30 mL/min/1.73 m2 should receive the dosages recommended under Normal Renal Function. Elderly patients being treated for urinary tract infections who have a creatinine clearance of 30 mL/min/1.73 m2 or less should receive 400 mg once daily as recommended under Renal Impairment. HOW SUPPLIED No. 8338 — Tablets NOROXIN 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20. Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. ANIMAL PHARMACOLOGY Norfloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested (see W ARNINGS). Crystalluria has occurred in laboratory animals tested with norfloxacin. In dogs, needle-shaped drug crystals were seen in the urine at doses of 50 mg/kg/day. In rats, crystals were reported following doses of 200 mg/kg/day. Embryo lethality and slight maternotoxicity (vomiting and anorexia) were observed in cynomolgus monkeys at doses of 150 mg/kg/day or higher. Ocular toxicity, seen with some related drugs, was not observed in any norfloxacin-treated animals. 13 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda REFERENCES 1. Clinical and Laboratory Standards Institute, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - Eighth edition, Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, 2009. 2. Clinical and Laboratory Standards Institute, Performance standards for antimicrobial disk susceptibility tests - Tenth edition, Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, 2009. company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. Revised: 07/2016 uspi-mk0366-t-1606r012 14 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda MEDICATION GUIDE NOROXIN® [nor-AHK-sin] (norfloxacin) Tablets Read the Medication Guide that comes with NOROXIN® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about NOROXIN? NOROXIN belongs to a class of antibiotics called fluoroquinolones. NOROXIN can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you develop any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take NOROXIN. 1. Tendon rupture or swelling of the tendon (tendinitis) • Tendon problems can happen in people of all ages who take NOROXIN. Tendons are tough cords of tissue that connect muscle to bones. Symptoms of tendon problems may include: • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. • The risk of getting tendon problems while you take NOROXIN is higher if you: • are over 60 years of age • are taking steroids (corticosteroids) • have had a kidney, heart or lung transplant • Tendon problems can happen in people who do not have the above risk factors when they take NOROXIN. Other reasons that can increase your risk of tendon problems can include: • physical activity or exercise • kidney failure • tendon problems in the past, such as in people with rheumatoid arthritis (RA) • Stop taking NOROXIN immediately and get medical help right away at the first sign of tendon pain, swelling or inflammation. Stop taking NOROXIN until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. • Talk to your healthcare provider about the risk of tendon rupture with continued use of NOROXIN. You may need a different antibiotic that is not a fluoroquinolone to treat your infection. • Tendon rupture can happen while you are taking or after you have finished taking NOROXIN. Tendon ruptures can happen within hours or days of taking NOROXIN, and have happened up to several months after patients have finished taking their fluoroquinolone. • Get medical help right away if you get any of the following signs or symptoms of a tendon rupture: • hear or feel a snap or pop in a tendon area • bruising right after an incident in a tendon area • unable to move the affected area or bear weight Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including NOROXIN. Stop taking NOROXIN immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: • pain • numbness • burning • weakness • tingling NOROXIN may need to be stopped to prevent permanent nerve damage. 3. Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including NOROXIN. Tell your healthcare provider if you have a history of seizures before you start taking NOROXIN. CNS side effects may happen as soon as after taking the first dose of NOROXIN. Stop taking NOROXIN immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: • seizures • trouble sleeping • hear voices, see things, or sense things • nightmares that are not there (hallucinations) • feel lightheaded or dizzy • feel restless • feel more suspicious (paranoia) • tremors • suicidal thoughts or acts • feel anxious or nervous • headaches that will not go away, with or • confusion without blurred vision • depression 4. Worsening of myasthenia gravis (a disease which causes muscle weakness) Fluoroquinolones like NOROXIN may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking NOROXIN. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. See the section "What are the possible side effects of NOROXIN?" for more information about side effects. What is NOROXIN? NOROXIN is a fluoroquinolone antibiotic medicine used in adults to treat certain infections caused by certain germs called bacteria. It is not known if NOROXIN is safe and works in children under 18 years of age. Children have a higher chance of getting bone and joint (musculoskeletal) problems while taking NOROXIN. Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics including NOROXIN do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking NOROXIN. Who should not take NOROXIN? Do not take NOROXIN if you: 2 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in NOROXIN. Ask your healthcare provider if you are not sure. See the list of ingredients in NOROXIN at the end of this Medication Guide. • have had tendinitis or tendon rupture with the use of NOROXIN or another fluoroquinolone antibiotic. What should I tell my healthcare provider before taking NOROXIN? See “What is the most important information I should know about NOROXIN?” Tell your healthcare provider about all your medical conditions, including if you: • have tendon problems. NOROXIN should not be used in patients who have a history of tendon problems • have nerve problems. NOROXIN should not be used in patients who have a history of nerve problems called peripheral neuropathy • have central nervous system problems (such as epilepsy) • have a disease that causes muscle weakness (myasthenia gravis). NOROXIN should not be used in patients who have a known history of myasthenia gravis • have or anyone in your family has an irregular heartbeat, especially a condition called “QTc prolongation” • have low potassium (hypokalemia) • have a slow heartbeat called bradycardia • have a history of seizures • have kidney problems. You may need a lower dose of NOROXIN if your kidneys do not work well. • have rheumatoid arthritis (RA) or other history of joint problems • are pregnant or planning to become pregnant. It is not known if NOROXIN will harm your unborn child. • are breast-feeding or planning to breast-feed. It is not known if NOROXIN passes into breast milk. You and your healthcare provider should decide whether you will take NOROXIN or breast-feed. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal and dietary supplements. NOROXIN and other medicines 1 can affect each other causing side effects. Especially tell your healthcare provider if you take: • an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take NOROXIN or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See "What are the possible side effects of NOROXIN?" • glyburide (Micronase, Glynase, Diabeta, Glucovance). See "What are the possible side effects of NOROXIN?" • a blood thinner (warfarin, Coumadin, Jantoven) • a medicine to control your heart rate or rhythm (antiarrhythmics). See "What are the possible side effects of NOROXIN?" • an anti-psychotic medicine • a tricyclic antidepressant • erythromycin • a water pill (diuretic) • a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. • probenecid (Probalan, Col-probenecid) • cyclosporine (Gengraf, Sandimmune, Neoral) 1 Other brands listed are the trademarks of their respective owners and are not trademarks of Merck Sharp & Dohme Corp. 3 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • products that contain caffeine • clozapine (Fazaclo ODT, Clozaril) • ropinirole (Requip, Requip XL) • tacrine (Cognex) • tizanidine (Zanaflex) • theophylline (Theo-24, Elixophyllin, Theochron, Uniphyl, Theolair) • cisapride (Propulsid) • certain medicines may keep NOROXIN from working correctly. Take NOROXIN either 2 hours before or 2 hours after taking these products: • an antacid, multivitamin or other product that has iron or zinc • sucralfate (Carafate) • didanosine (Videx, Videx EC) • You should not take the medicine nitrofurantoin (Furadantin, Macrodantin, Macrobid) while taking NOROXIN. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take NOROXIN? • Take NOROXIN exactly as prescribed by your healthcare provider. • NOROXIN is usually taken every 12 hours for patients with normal kidney function. • Take NOROXIN with a glass of water. • Drink plenty of fluids while taking NOROXIN. • Take NOROXIN at least one hour before or 2 hours after a meal or having milk or other dairy products. • Do not skip any doses, or stop taking NOROXIN even if you begin to feel better, until you finish your prescribed treatment, unless: • you have tendon effects (see “What is the most important information I should know about NOROXIN?”), • you have nerve problems (see “What is the most important information I should know about NOROXIN?”) • you have central nervous system problems (see “What is the most important information I should know about NOROXIN?”) • you have a serious allergic reaction (see “What are the possible side effects of NOROXIN?”), or • your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to NOROXIN. If this happens, NOROXIN and other antibiotic medicines may not work in the future. • If you miss a dose of NOROXIN, take it as soon as you remember. Do not take two doses of NOROXIN at the same time. Do not take more than 2 doses of NOROXIN in one day. • If you take too much, call your healthcare provider or get medical help immediately. What should I avoid while taking NOROXIN? • NOROXIN can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how NOROXIN affects you. • Avoid sunlamps and tanning beds, and try to limit your time in the sun. NOROXIN can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get 4 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking NOROXIN, call your healthcare provider right away. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of NOROXIN? NOROXIN can cause side effects that may be serious or even cause death. See “What is the most important information I should know about NOROXIN?” Other serious side effects of NOROXIN include: • Serious allergic reactions. Allergic reactions can happen in people who take fluoroquinolones, including NOROXIN, even after only one dose. Stop taking NOROXIN and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: • • hives • rapid heartbeat • trouble breathing or swallowing • faint • swelling of the lips, tongue, face • skin rash accompanied by fever and • throat tightness, hoarseness feeling unwell • yellowing of the skin or eyes. Stop taking NOROXIN and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to NOROXIN (a liver problem). • Skin rash. Skin rash may happen in people taking NOROXIN, even after only one dose. Stop taking NOROXIN at the first sign of a skin rash and call your healthcare provider. Skin rash may be sign of a more serious reaction to NOROXIN. • Serious heart rhythm changes (QTc prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. NOROXIN may cause a rare heart problem known as prolongation of the QTc interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: • who are elderly • with a family history of prolonged QTc interval • with low blood potassium (hypokalemia) • who take certain medicines to control heart rhythm (antiarrhythmics) • Intestine infection (Pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including NOROXIN. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic. • Low blood sugar (hypoglycemia). People taking NOROXIN and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar while taking NOROXIN. Your antibiotic medicine may need to be changed. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking NOROXIN?” The most common side effects of NOROXIN include: • dizziness 5 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • nausea • diarrhea • heartburn • headache • stomach (abdominal) cramping • weakness • changes in certain liver function tests These are not all the possible side effects of NOROXIN. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NOROXIN? Store at room temperature between 59-86°F (15-30°C). Keep container closed tightly. Keep NOROXIN and all medicines out of the reach of children. General Information about NOROXIN Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOROXIN for a condition for which it is not prescribed. Do not give NOROXIN to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about NOROXIN. If you would like more information about NOROXIN, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NOROXIN that is written for healthcare professionals. For more information call 1-800-622-4477. What are the ingredients in NOROXIN? Active ingredient: norfloxacin Inactive ingredients: cellulose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide company logo Manufactured by: Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 Pavia, Italy Copyright © 1986, 1989, 1999, 2001 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 6 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Revised: 07/2016 usmg-mk0366-t-1606r011 This Medication Guide has been approved by the U.S. Food and Drug Administration. 7 Reference ID: 3963463 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.745333	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019384s067lbl.pdf', 'application_number': 19384, 'submission_type': 'SUPPL ', 'submission_number': 67}
11,496	NDA 19-385 /S-030/ S-031/ S-035 Page 3 5.02 PV 2271-A UCP PERMAX® PERGOLIDE MESYLATE DESCRIPTION Permax (Pergolide Mesylate) is an ergot derivative dopamine receptor agonist at both D1 and D2 receptor sites. Pergolide mesylate is chemically designated as 8β-[(Methylthio)methyl]-6- propylergoline monomethanesulfonate; the structural formula is as follows: The empirical formula is C19H26N2S•CH4O3S, representing a molecular weight of 410.60. Permax is provided for oral administration in tablets containing 0.05 mg (0.159 µmol), 0.25 mg (0.795 µmol), or 1 mg (3.18 µmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05 mg tablet also contains L-methionine, and the 0.25 mg tablet also contains FD&C Blue No. 2. CLINICAL PHARMACOLOGY Pharmacodynamic Information Pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson’s disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating postsynaptic dopamine receptors in the nigrostriatal system. Pharmacokinetic Information (Absorption, Distribution, Metabolism, and Elimination) Information on oral systemic bioavailability of pergolide mesylate is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of 14C radiolabeled pergolide mesylate, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO2, suggesting that a significant fraction is absorbed. Nothing can be concluded about the extent of presystemic clearance, if any. Data on postabsorption distribution of pergolide are unavailable. At least 10 metabolites have been detected, including N-despropylpergolide, pergolide sulfoxide, and pergolide sulfone. Pergolide sulfoxide and pergolide sulfone are dopamine agonists in animals. The other detected metabolites have not been identified and it is not known whether any other metabolites are active pharmacologically. The major route of excretion is the kidney. HN N CH2SCH3 CH2CH2CH3 CH3SO3H H H H • This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 4 Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide mesylate is coadministered with other drugs known to affect protein binding. INDICATIONS AND USAGE Permax is indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson’s disease. Evidence to support the efficacy of pergolide mesylate as an antiparkinsonian adjunct was obtained in a multicenter study enrolling 376 patients with mild to moderate Parkinson’s disease who were intolerant to l-dopa/carbidopa as manifested by moderate to severe dyskinesia and/or on-off phenomena. On average, the patients evaluated had been on l-dopa/carbidopa for 3.9 years (range, 2 days to 16.8 years). The administration of pergolide mesylate permitted a 5% to 30% reduction in the daily dose of l-dopa. On average, these patients treated with pergolide mesylate maintained an equivalent or better clinical status than they exhibited at baseline. CONTRAINDICATIONS Pergolide mesylate is contraindicated in patients who are hypersensitive to this drug or other ergot derivatives. WARNINGS Falling Asleep During Activities of Daily Living — Patients treated with PERMAX have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on PERMAX, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as 1 year after the initiation of treatment. Somnolence is a common occurrence in patients receiving PERMAX. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with PERMAX, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with PERMAX such as concomitant sedating medications or the presence of sleep disorders. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require participation (e.g., conversations, eating, etc.), PERMAX should ordinarily be discontinued. If a decision is made to continue PERMAX, patients should be advised to not drive and to avoid other potentially dangerous activities. While dose reduction may reduce the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Symptomatic Hypotension — In clinical trials, approximately 10% of patients taking pergolide mesylate with l-dopa versus 7% taking placebo with l-dopa experienced symptomatic orthostatic and/or sustained hypotension, especially during initial treatment. With gradual dosage titration, tolerance to the hypotension usually develops. It is therefore important to warn patients of the risk, to begin therapy with low doses, and to increase the dosage in carefully adjusted increments over a period of 3 to 4 weeks (see Dosage and Administration). Hallucinosis — In controlled trials, pergolide mesylate with l-dopa caused hallucinosis in about 14% of patients as opposed to 3% taking placebo with l-dopa. This was of sufficient This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 5 severity to cause discontinuation of treatment in about 3% of those enrolled; tolerance to this untoward effect was not observed. Fatalities — In the placebo-controlled trial, 2 of 187 patients treated with placebo died as compared with 1 of 189 patients treated with pergolide mesylate. Of the 2299 patients treated with pergolide mesylate in premarketing studies evaluated as of October 1988, 143 died while on the drug or shortly after discontinuing it. Because the patient population under evaluation was elderly, ill, and at high risk for death, it seems unlikely that pergolide mesylate played any role in these deaths, but the possibility that pergolide shortens survival of patients cannot be excluded with absolute certainty. In particular, a case-by-case review of the clinical course of the patients who died failed to disclose any unique set of signs, symptoms, or laboratory results that would suggest that treatment with pergolide caused their deaths. Sixty-eight percent (68%) of the patients who died were 65 years of age or older. No death (other than a suicide) occurred within the first month of treatment; most of the patients who died had been on pergolide for years. A relative frequency of the causes of death by organ system are: Pulmonary failure/Pneumonia, 35%; Cardiovascular, 30%; Cancer, 11%; Unknown, 8.4%; Infection, 3.5%; Extrapyramidal syndrome, 3.5%; Stroke, 2.1%; Dysphagia, 2.1%; Injury, 1.4%; Suicide, 1.4%; Dehydration, 0.7%; Glomerulonephritis, 0.7%. Serous Inflammation and Fibrosis — There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide. Pergolide should be used with caution in patients with a history of these conditions, particularly those patients who experienced the events while taking ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide. PRECAUTIONS General Caution should be exercised when administering pergolide mesylate to patients prone to cardiac dysrhythmias. In a study comparing pergolide mesylate and placebo, patients taking pergolide mesylate were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia. The use of pergolide mesylate in patients on l-dopa may cause and/or exacerbate preexisting states of confusion and hallucinations (see Warnings) and preexisting dyskinesia. Also, the abrupt discontinuation of pergolide mesylate in patients receiving it chronically as an adjunct to l-dopa may precipitate the onset of hallucinations and confusion; these may occur within a span of several days. Discontinuation of pergolide should be undertaken gradually whenever possible, even if the patient is to remain on l-dopa. A symptom complex resembling the neuroleptic malignant syndrome (NMS) (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy, including pergolide. Information for Patients Because pergolide mesylate may cause somnolence and the possibility of falling asleep during activities of daily living, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that pergolide mesylate therapy does not affect them adversely. Patients should be advised that if increased somnolence or new episodes This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 6 of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Due to the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with pergolide mesylate. Patients and their families should be informed of the common adverse consequences of the use of pergolide mesylate (see Adverse Reactions) and the risk of hypotension (see Warnings). Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant. Laboratory Tests No specific laboratory tests are deemed essential for the management of patients on Permax. Periodic routine evaluation of all patients, however, is appropriate. Drug Interactions Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. Carcinogenesis, Mutagenesis, and Impairment of Fertility A 2-year carcinogenicity study was conducted in mice using dietary levels of pergolide mesylate equivalent to oral doses of 0.6, 3.7, and 36.4 mg/kg/day in males and 0.6, 4.4, and 40.8 mg/kg/day in females. A 2-year study in rats was conducted using dietary levels equivalent to oral doses of 0.04, 0.18, and 0.88 mg/kg/day in males and 0.05, 0.28, and 1.42 mg/kg/day in females. The highest doses tested in the mice and rats were approximately 340 and 12 times the maximum human oral dose administered in controlled clinical trials (6 mg/day equivalent to 0.12 mg/kg/day). A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio that would occur in rodents as a result of the prolactin-inhibiting action of pergolide mesylate. The endocrine mechanisms believed to be involved in the rodents are not present in humans. However, even though there is no known correlation between uterine malignancies occurring in pergolide-treated rodents and human risk, there are no human data to substantiate this conclusion. Pergolide mesylate was evaluated for mutagenic potential in a battery of tests that included an Ames bacterial mutation assay, a DNA repair assay in cultured rat hepatocytes, an in vitro mammalian cell gene mutation assay in cultured L5178Y cells, and a determination of chromosome alteration in bone marrow cells of Chinese hamsters. A weak mutagenic response was noted in the mammalian cell gene mutation assay only after metabolic activation with rat liver microsomes. No mutagenic effects were obtained in the 2 other in vitro assays and in the in vivo assay. The relevance of these findings in humans is unknown. A fertility study in male and female mice showed that fertility was maintained at 0.6 and 1.7 mg/kg/day but decreased at 5.6 mg/kg/day. Prolactin has been reported to be involved in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 7 stimulating and maintaining progesterone levels required for implantation in mice and, therefore, the impaired fertility at the high dose may have occurred because of depressed prolactin levels. Usage in Pregnancy — Pregnancy Category B Reproduction studies were conducted in mice at doses of 5, 16, and 45 mg/kg/day and in rabbits at doses of 2, 6, and 16 mg/kg/day. The highest doses tested in mice and rabbits were 375 and 133 times the 6 mg/day maximum human dose administered in controlled clinical trials. In these studies, there was no evidence of harm to the fetus due to pergolide mesylate. There are, however, no adequate and well-controlled studies in pregnant women. Among women who received pergolide mesylate for endocrine disorders in premarketing studies, there were 33 pregnancies that resulted in healthy babies and 6 pregnancies that resulted in congenital abnormalities (3 major, 3 minor); a causal relationship has not been established. Because human data are limited and because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. The pharmacologic action of pergolide mesylate suggests that it may interfere with lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to pergolide mesylate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of pergolide mesylate, 78 were 65 and over. There were no apparent differences in efficacy between these subjects and younger subjects. There was an increased incidence of confusion, somnolence, and peripheral edema in patients 65 and over. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Commonly Observed — In premarketing clinical trials, the most commonly observed adverse events associated with use of pergolide mesylate which were not seen at an equivalent incidence among placebo-treated patients were: nervous system complaints, including dyskinesia, hallucinations, somnolence, insomnia; digestive complaints, including nausea, constipation, diarrhea, dyspepsia; and respiratory system complaints, including rhinitis. Associated With Discontinuation of Treatment — Twenty-seven percent (27%) of approximately 1200 patients receiving pergolide mesylate for treatment of Parkinson’s disease in premarketing clinical trials in the US and Canada discontinued treatment due to adverse events. The events most commonly causing discontinuation were related to the nervous system (15.5%), primarily hallucinations (7.8%) and confusion (1.8%). Fatalities — See Warnings. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 8 Incidence in Controlled Clinical Trials — The table that follows enumerates adverse events that occurred at a frequency of 1% or more among patients taking pergolide mesylate who participated in the premarketing controlled clinical trials comparing pergolide mesylate with placebo. In a double-blind, controlled study of 6 months’ duration, patients with Parkinson’s disease were continued on l-dopa/carbidopa and were randomly assigned to receive either pergolide mesylate or placebo as additional therapy. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. Incidence of Treatment-Emergent Adverse Experiences in the Placebo-Controlled Clinical Trial Percentage of Patients Reporting Events Pergolide Mesylate Placebo Body System/Adverse Event* N=189 N=187 Body as a Whole Pain 7.0 2.1 Abdominal pain 5.8 2.1 Injury, accident 5.8 7.0 Headache 5.3 6.4 Asthenia 4.2 4.8 Chest pain 3.7 2.1 Flu syndrome 3.2 2.1 Neck pain 2.7 1.6 Back pain 1.6 2.1 Surgical procedure 1.6 <1 Chills 1.1 0 Face edema 1.1 0 Infection 1.1 0 Cardiovascular Postural hypotension 9.0 7.0 Vasodilatation 3.2 <1 Palpitation 2.1 <1 Hypotension 2.1 <1 Syncope 2.1 1.1 Hypertension 1.6 1.1 Arrhythmia 1.1 <1 Myocardial infarction 1.1 <1 Digestive Nausea 24.3 12.8 Constipation 10.6 5.9 Diarrhea 6.4 2.7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 9 Dyspepsia 6.4 2.1 Anorexia 4.8 2.7 Dry mouth 3.7 <1 Vomiting 2.7 1.6 Hemic and Lymphatic Anemia 1.1 <1 Metabolic and Nutritional Peripheral edema 7.4 4.3 Edema 1.6 0 Weight gain 1.6 0 Musculoskeletal Arthralgia 1.6 2.1 Bursitis 1.6 <1 Myalgia 1.1 <1 Twitching 1.1 0 Nervous System Dyskinesia 62.4 24.6 Dizziness 19.1 13.9 Hallucinations 13.8 3.2 Dystonia 11.6 8.0 Confusion 11.1 9.6 Somnolence 10.1 3.7 Insomnia 7.9 3.2 Anxiety 6.4 4.3 Tremor 4.2 7.5 Depression 3.2 5.4 Abnormal dreams 2.7 4.3 Personality disorder 2.1 <1 Psychosis 2.1 0 Abnormal gait 1.6 1.6 Akathisia 1.6 0 Extrapyramidal syndrome 1.6 1.1 Incoordination 1.6 <1 Paresthesia 1.6 3.2 Akinesia 1.1 1.1 Hypertonia 1.1 0 Neuralgia 1.1 <1 Speech disorder 1.1 1.6 Respiratory System Rhinitis 12.2 5.4 Dyspnea 4.8 1.1 Epistaxis 1.6 <1 Hiccup 1.1 0 Skin and Appendages Rash 3.2 2.1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 10 Sweating 2.1 2.7 Special Senses Abnormal vision 5.8 5.4 Diplopia 2.1 0 Taste perversion 1.6 0 Eye disorder 1.1 0 Urogenital System Urinary frequency 2.7 6.4 Urinary tract infection 2.7 3.7 Hematuria 1.1 <1 * Events reported by at least 1% of patients receiving pergolide mesylate are included. Events Observed During the Premarketing Evaluation of Permax — This section reports event frequencies evaluated as of October 1988 for adverse events occurring in a group of approximately 1800 patients who took multiple doses of pergolide mesylate. The conditions and duration of exposure to pergolide mesylate varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. In the absence of appropriate controls in some of the studies, a causal relationship between these events and treatment with pergolide mesylate cannot be determined. The following enumeration by organ system describes events in terms of their relative frequency of reporting in the data base. Events of major clinical importance are also described in the Warnings and Precautions sections. The following definitions of frequency are used: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent: headache, asthenia, accidental injury, pain, abdominal pain, chest pain, back pain, flu syndrome, neck pain, fever; Infrequent: facial edema, chills, enlarged abdomen, malaise, neoplasm, hernia, pelvic pain, sepsis, cellulitis, moniliasis, abscess, jaw pain, hypothermia; Rare: acute abdominal syndrome, LE syndrome. Cardiovascular System — Frequent: postural hypotension, syncope, hypertension, palpitations, vasodilatations, congestive heart failure; Infrequent: myocardial infarction, tachycardia, heart arrest, abnormal electrocardiogram, angina pectoris, thrombophlebitis, bradycardia, ventricular extrasystoles, cerebrovascular accident, ventricular tachycardia, cerebral ischemia, atrial fibrillation, varicose vein, pulmonary embolus, AV block, shock; Rare: vasculitis, pulmonary hypertension, pericarditis, migraine, heart block, cerebral hemorrhage. Digestive System — Frequent: nausea, vomiting, dyspepsia, diarrhea, constipation, dry mouth, dysphagia; Infrequent: flatulence, abnormal liver function tests, increased appetite, salivary gland enlargement, thirst, gastroenteritis, gastritis, periodontal abscess, intestinal obstruction, nausea and vomiting, gingivitis, esophagitis, cholelithiasis, tooth caries, hepatitis, stomach ulcer, melena, hepatomegaly, hematemesis, eructation; Rare: sialadenitis, peptic ulcer, pancreatitis, jaundice, glossitis, fecal incontinence, duodenitis, colitis, cholecystitis, aphthous stomatitis, esophageal ulcer. Endocrine System — Infrequent: hypothyroidism, adenoma, diabetes mellitus, ADH inappropriate; Rare: endocrine disorder, thyroid adenoma. Hemic and Lymphatic System — Frequent: anemia; Infrequent: leukopenia, lymphadenopathy, leukocytosis, thrombocytopenia, petechia, megaloblastic anemia, cyanosis; This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 11 Rare: purpura, lymphocytosis, eosinophilia, thrombocythemia, acute lymphoblastic leukemia, polycythemia, splenomegaly. Metabolic and Nutritional System — Frequent: peripheral edema, weight loss, weight gain; Infrequent: dehydration, hypokalemia, hypoglycemia, iron deficiency anemia, hyperglycemia, gout, hypercholesteremia; Rare: electrolyte imbalance, cachexia, acidosis, hyperuricemia. Musculoskeletal System — Frequent: twitching, myalgia, arthralgia; Infrequent: bone pain, tenosynovitis, myositis, bone sarcoma, arthritis; Rare: osteoporosis, muscle atrophy, osteomyelitis. Nervous System — Frequent: dyskinesia, dizziness, hallucinations, confusion, somnolence, insomnia, dystonia, paresthesia, depression, anxiety, tremor, akinesia, extrapyramidal syndrome, abnormal gait, abnormal dreams, incoordination, psychosis, personality disorder, nervousness, choreoathetosis, amnesia, paranoid reaction, abnormal thinking; Infrequent: akathisia, neuropathy, neuralgia, hypertonia, delusions, convulsion, libido increased, euphoria, emotional lability, libido decreased, vertigo, myoclonus, coma, apathy, paralysis, neurosis, hyperkinesia, ataxia, acute brain syndrome, torticollis, meningitis, manic reaction, hypokinesia, hostility, agitation, hypotonia; Rare: stupor, neuritis, intracranial hypertension, hemiplegia, facial paralysis, brain edema, myelitis, hallucinations and confusion after abrupt discontinuation. Respiratory System — Frequent: rhinitis, dyspnea, pneumonia, pharyngitis, cough increased; Infrequent: epistaxis, hiccup, sinusitis, bronchitis, voice alteration, hemoptysis, asthma, lung edema, pleural effusion, laryngitis, emphysema, apnea, hyperventilation; Rare: pneumothorax, lung fibrosis, larynx edema, hypoxia, hypoventilation, hemothorax, carcinoma of lung. Skin and Appendages System — Frequent: sweating, rash; Infrequent: skin discoloration, pruritus, acne, skin ulcer, alopecia, dry skin, skin carcinoma, seborrhea, hirsutism, herpes simplex, eczema, fungal dermatitis, herpes zoster; Rare: vesiculobullous rash, subcutaneous nodule, skin nodule, skin benign neoplasm, lichenoid dermatitis. Special Senses System — Frequent: abnormal vision, diplopia; Infrequent: otitis media, conjunctivitis, tinnitus, deafness, taste perversion, ear pain, eye pain, glaucoma, eye hemorrhage, photophobia, visual field defect; Rare: blindness, cataract, retinal detachment, retinal vascular disorder. Urogenital System — Frequent: urinary tract infection, urinary frequency, urinary incontinence, hematuria, dysmenorrhea; Infrequent: dysuria, breast pain, menorrhagia, impotence, cystitis, urinary retention, abortion, vaginal hemorrhage, vaginitis, priapism, kidney calculus, fibrocystic breast, lactation, uterine hemorrhage, urolithiasis, salpingitis, pyuria, metrorrhagia, menopause, kidney failure, breast carcinoma, cervical carcinoma; Rare: amenorrhea, bladder carcinoma, breast engorgement, epididymitis, hypogonadism, leukorrhea, nephrosis, pyelonephritis, urethral pain, uricaciduria, withdrawal bleeding. Postintroduction Reports — Voluntary reports of adverse events temporally associated with pergolide that have been received since market introduction and which may have no causal relationship with the drug, include the following: neuroleptic malignant syndrome. OVERDOSAGE There is no clinical experience with massive overdosage. The largest overdose involved a young hospitalized adult patient who was not being treated with pergolide mesylate but who intentionally took 60 mg of the drug. He experienced vomiting, hypotension, and agitation. Another patient receiving a daily dosage of 7 mg of pergolide mesylate unintentionally took 19 mg/day for 3 days, after which his vital signs were normal but he experienced severe hallucinations. Within 36 hours of resumption of the prescribed dosage level, the hallucinations stopped. One patient unintentionally took 14 mg/day for 23 days instead of her prescribed 1.4 mg/day dosage. She experienced severe involuntary movements and tingling in her arms and legs. Another patient who inadvertently received 7 mg instead of the prescribed 0.7 mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 12 experienced palpitations, hypotension, and ventricular extrasystoles. The highest total daily dose (prescribed for several patients with refractory Parkinson’s disease) has exceeded 30 mg. Symptoms — Animal studies indicate that the manifestations of overdosage in man might include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation. The oral median lethal doses in mice and rats were 54 and 15 mg/kg respectively. Treatment — To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Management of overdosage may require supportive measures to maintain arterial blood pressure. Cardiac function should be monitored; an antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdose has not been assessed. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. There is no experience with dialysis or hemoperfusion, and these procedures are unlikely to be of benefit. DOSAGE AND ADMINISTRATION Administration of Permax should be initiated with a daily dosage of 0.05 mg for the first 2 days. The dosage should then be gradually increased by 0.1 or 0.15 mg/day every third day over the next 12 days of therapy. The dosage may then be increased by 0.25 mg/day every third day until an optimal therapeutic dosage is achieved. Permax is usually administered in divided doses 3 times per day. During dosage titration, the dosage of concurrent l-dopa/carbidopa may be cautiously decreased. In clinical studies, the mean therapeutic daily dosage of Permax was 3 mg/day. The average concurrent daily dosage of l-dopa/carbidopa (expressed as l-dopa) was approximately 650 mg/day. The efficacy of Permax at doses above 5 mg/day has not been systematically evaluated. HOW SUPPLIED Tablets (modified rectangle shape, scored): 0.05 mg, ivory, debossed with A 024, in bottles of 30 (UC5336) — NDC 65234-024-30 0.25 mg, green, debossed with A 025, in bottles of 100 (UC5337) — NDC 65234-025-10 1 mg, pink, debossed with A 026, in bottles of 100 (UC5338) — NDC 65234-026-10 _________________ Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. PERMAX is a registered trademark of Eli Lilly and Company, and licensed in the US to Amarin Pharmaceuticals, Inc. Literature revised This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 13 Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA Distributed by: Amarin Pharmaceuticals, Inc. Mill Valley, CA 94941 This label may not be the latest approved by FDA. 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11,497	NDA 19-385 /S-030/ S-031/ S-035 Page 3 5.02 PV 2271-A UCP PERMAX® PERGOLIDE MESYLATE DESCRIPTION Permax (Pergolide Mesylate) is an ergot derivative dopamine receptor agonist at both D1 and D2 receptor sites. Pergolide mesylate is chemically designated as 8β-[(Methylthio)methyl]-6- propylergoline monomethanesulfonate; the structural formula is as follows: The empirical formula is C19H26N2S•CH4O3S, representing a molecular weight of 410.60. Permax is provided for oral administration in tablets containing 0.05 mg (0.159 µmol), 0.25 mg (0.795 µmol), or 1 mg (3.18 µmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05 mg tablet also contains L-methionine, and the 0.25 mg tablet also contains FD&C Blue No. 2. CLINICAL PHARMACOLOGY Pharmacodynamic Information Pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson’s disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating postsynaptic dopamine receptors in the nigrostriatal system. Pharmacokinetic Information (Absorption, Distribution, Metabolism, and Elimination) Information on oral systemic bioavailability of pergolide mesylate is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of 14C radiolabeled pergolide mesylate, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO2, suggesting that a significant fraction is absorbed. Nothing can be concluded about the extent of presystemic clearance, if any. Data on postabsorption distribution of pergolide are unavailable. At least 10 metabolites have been detected, including N-despropylpergolide, pergolide sulfoxide, and pergolide sulfone. Pergolide sulfoxide and pergolide sulfone are dopamine agonists in animals. The other detected metabolites have not been identified and it is not known whether any other metabolites are active pharmacologically. The major route of excretion is the kidney. HN N CH2SCH3 CH2CH2CH3 CH3SO3H H H H • This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 4 Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide mesylate is coadministered with other drugs known to affect protein binding. INDICATIONS AND USAGE Permax is indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson’s disease. Evidence to support the efficacy of pergolide mesylate as an antiparkinsonian adjunct was obtained in a multicenter study enrolling 376 patients with mild to moderate Parkinson’s disease who were intolerant to l-dopa/carbidopa as manifested by moderate to severe dyskinesia and/or on-off phenomena. On average, the patients evaluated had been on l-dopa/carbidopa for 3.9 years (range, 2 days to 16.8 years). The administration of pergolide mesylate permitted a 5% to 30% reduction in the daily dose of l-dopa. On average, these patients treated with pergolide mesylate maintained an equivalent or better clinical status than they exhibited at baseline. CONTRAINDICATIONS Pergolide mesylate is contraindicated in patients who are hypersensitive to this drug or other ergot derivatives. WARNINGS Falling Asleep During Activities of Daily Living — Patients treated with PERMAX have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on PERMAX, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as 1 year after the initiation of treatment. Somnolence is a common occurrence in patients receiving PERMAX. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with PERMAX, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with PERMAX such as concomitant sedating medications or the presence of sleep disorders. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require participation (e.g., conversations, eating, etc.), PERMAX should ordinarily be discontinued. If a decision is made to continue PERMAX, patients should be advised to not drive and to avoid other potentially dangerous activities. While dose reduction may reduce the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Symptomatic Hypotension — In clinical trials, approximately 10% of patients taking pergolide mesylate with l-dopa versus 7% taking placebo with l-dopa experienced symptomatic orthostatic and/or sustained hypotension, especially during initial treatment. With gradual dosage titration, tolerance to the hypotension usually develops. It is therefore important to warn patients of the risk, to begin therapy with low doses, and to increase the dosage in carefully adjusted increments over a period of 3 to 4 weeks (see Dosage and Administration). Hallucinosis — In controlled trials, pergolide mesylate with l-dopa caused hallucinosis in about 14% of patients as opposed to 3% taking placebo with l-dopa. This was of sufficient This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 5 severity to cause discontinuation of treatment in about 3% of those enrolled; tolerance to this untoward effect was not observed. Fatalities — In the placebo-controlled trial, 2 of 187 patients treated with placebo died as compared with 1 of 189 patients treated with pergolide mesylate. Of the 2299 patients treated with pergolide mesylate in premarketing studies evaluated as of October 1988, 143 died while on the drug or shortly after discontinuing it. Because the patient population under evaluation was elderly, ill, and at high risk for death, it seems unlikely that pergolide mesylate played any role in these deaths, but the possibility that pergolide shortens survival of patients cannot be excluded with absolute certainty. In particular, a case-by-case review of the clinical course of the patients who died failed to disclose any unique set of signs, symptoms, or laboratory results that would suggest that treatment with pergolide caused their deaths. Sixty-eight percent (68%) of the patients who died were 65 years of age or older. No death (other than a suicide) occurred within the first month of treatment; most of the patients who died had been on pergolide for years. A relative frequency of the causes of death by organ system are: Pulmonary failure/Pneumonia, 35%; Cardiovascular, 30%; Cancer, 11%; Unknown, 8.4%; Infection, 3.5%; Extrapyramidal syndrome, 3.5%; Stroke, 2.1%; Dysphagia, 2.1%; Injury, 1.4%; Suicide, 1.4%; Dehydration, 0.7%; Glomerulonephritis, 0.7%. Serous Inflammation and Fibrosis — There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide. Pergolide should be used with caution in patients with a history of these conditions, particularly those patients who experienced the events while taking ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide. PRECAUTIONS General Caution should be exercised when administering pergolide mesylate to patients prone to cardiac dysrhythmias. In a study comparing pergolide mesylate and placebo, patients taking pergolide mesylate were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia. The use of pergolide mesylate in patients on l-dopa may cause and/or exacerbate preexisting states of confusion and hallucinations (see Warnings) and preexisting dyskinesia. Also, the abrupt discontinuation of pergolide mesylate in patients receiving it chronically as an adjunct to l-dopa may precipitate the onset of hallucinations and confusion; these may occur within a span of several days. Discontinuation of pergolide should be undertaken gradually whenever possible, even if the patient is to remain on l-dopa. A symptom complex resembling the neuroleptic malignant syndrome (NMS) (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy, including pergolide. Information for Patients Because pergolide mesylate may cause somnolence and the possibility of falling asleep during activities of daily living, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that pergolide mesylate therapy does not affect them adversely. Patients should be advised that if increased somnolence or new episodes This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 6 of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Due to the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with pergolide mesylate. Patients and their families should be informed of the common adverse consequences of the use of pergolide mesylate (see Adverse Reactions) and the risk of hypotension (see Warnings). Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant. Laboratory Tests No specific laboratory tests are deemed essential for the management of patients on Permax. Periodic routine evaluation of all patients, however, is appropriate. Drug Interactions Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. Carcinogenesis, Mutagenesis, and Impairment of Fertility A 2-year carcinogenicity study was conducted in mice using dietary levels of pergolide mesylate equivalent to oral doses of 0.6, 3.7, and 36.4 mg/kg/day in males and 0.6, 4.4, and 40.8 mg/kg/day in females. A 2-year study in rats was conducted using dietary levels equivalent to oral doses of 0.04, 0.18, and 0.88 mg/kg/day in males and 0.05, 0.28, and 1.42 mg/kg/day in females. The highest doses tested in the mice and rats were approximately 340 and 12 times the maximum human oral dose administered in controlled clinical trials (6 mg/day equivalent to 0.12 mg/kg/day). A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio that would occur in rodents as a result of the prolactin-inhibiting action of pergolide mesylate. The endocrine mechanisms believed to be involved in the rodents are not present in humans. However, even though there is no known correlation between uterine malignancies occurring in pergolide-treated rodents and human risk, there are no human data to substantiate this conclusion. Pergolide mesylate was evaluated for mutagenic potential in a battery of tests that included an Ames bacterial mutation assay, a DNA repair assay in cultured rat hepatocytes, an in vitro mammalian cell gene mutation assay in cultured L5178Y cells, and a determination of chromosome alteration in bone marrow cells of Chinese hamsters. A weak mutagenic response was noted in the mammalian cell gene mutation assay only after metabolic activation with rat liver microsomes. No mutagenic effects were obtained in the 2 other in vitro assays and in the in vivo assay. The relevance of these findings in humans is unknown. A fertility study in male and female mice showed that fertility was maintained at 0.6 and 1.7 mg/kg/day but decreased at 5.6 mg/kg/day. Prolactin has been reported to be involved in This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 7 stimulating and maintaining progesterone levels required for implantation in mice and, therefore, the impaired fertility at the high dose may have occurred because of depressed prolactin levels. Usage in Pregnancy — Pregnancy Category B Reproduction studies were conducted in mice at doses of 5, 16, and 45 mg/kg/day and in rabbits at doses of 2, 6, and 16 mg/kg/day. The highest doses tested in mice and rabbits were 375 and 133 times the 6 mg/day maximum human dose administered in controlled clinical trials. In these studies, there was no evidence of harm to the fetus due to pergolide mesylate. There are, however, no adequate and well-controlled studies in pregnant women. Among women who received pergolide mesylate for endocrine disorders in premarketing studies, there were 33 pregnancies that resulted in healthy babies and 6 pregnancies that resulted in congenital abnormalities (3 major, 3 minor); a causal relationship has not been established. Because human data are limited and because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. The pharmacologic action of pergolide mesylate suggests that it may interfere with lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to pergolide mesylate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of pergolide mesylate, 78 were 65 and over. There were no apparent differences in efficacy between these subjects and younger subjects. There was an increased incidence of confusion, somnolence, and peripheral edema in patients 65 and over. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Commonly Observed — In premarketing clinical trials, the most commonly observed adverse events associated with use of pergolide mesylate which were not seen at an equivalent incidence among placebo-treated patients were: nervous system complaints, including dyskinesia, hallucinations, somnolence, insomnia; digestive complaints, including nausea, constipation, diarrhea, dyspepsia; and respiratory system complaints, including rhinitis. Associated With Discontinuation of Treatment — Twenty-seven percent (27%) of approximately 1200 patients receiving pergolide mesylate for treatment of Parkinson’s disease in premarketing clinical trials in the US and Canada discontinued treatment due to adverse events. The events most commonly causing discontinuation were related to the nervous system (15.5%), primarily hallucinations (7.8%) and confusion (1.8%). Fatalities — See Warnings. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 8 Incidence in Controlled Clinical Trials — The table that follows enumerates adverse events that occurred at a frequency of 1% or more among patients taking pergolide mesylate who participated in the premarketing controlled clinical trials comparing pergolide mesylate with placebo. In a double-blind, controlled study of 6 months’ duration, patients with Parkinson’s disease were continued on l-dopa/carbidopa and were randomly assigned to receive either pergolide mesylate or placebo as additional therapy. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. Incidence of Treatment-Emergent Adverse Experiences in the Placebo-Controlled Clinical Trial Percentage of Patients Reporting Events Pergolide Mesylate Placebo Body System/Adverse Event* N=189 N=187 Body as a Whole Pain 7.0 2.1 Abdominal pain 5.8 2.1 Injury, accident 5.8 7.0 Headache 5.3 6.4 Asthenia 4.2 4.8 Chest pain 3.7 2.1 Flu syndrome 3.2 2.1 Neck pain 2.7 1.6 Back pain 1.6 2.1 Surgical procedure 1.6 <1 Chills 1.1 0 Face edema 1.1 0 Infection 1.1 0 Cardiovascular Postural hypotension 9.0 7.0 Vasodilatation 3.2 <1 Palpitation 2.1 <1 Hypotension 2.1 <1 Syncope 2.1 1.1 Hypertension 1.6 1.1 Arrhythmia 1.1 <1 Myocardial infarction 1.1 <1 Digestive Nausea 24.3 12.8 Constipation 10.6 5.9 Diarrhea 6.4 2.7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 9 Dyspepsia 6.4 2.1 Anorexia 4.8 2.7 Dry mouth 3.7 <1 Vomiting 2.7 1.6 Hemic and Lymphatic Anemia 1.1 <1 Metabolic and Nutritional Peripheral edema 7.4 4.3 Edema 1.6 0 Weight gain 1.6 0 Musculoskeletal Arthralgia 1.6 2.1 Bursitis 1.6 <1 Myalgia 1.1 <1 Twitching 1.1 0 Nervous System Dyskinesia 62.4 24.6 Dizziness 19.1 13.9 Hallucinations 13.8 3.2 Dystonia 11.6 8.0 Confusion 11.1 9.6 Somnolence 10.1 3.7 Insomnia 7.9 3.2 Anxiety 6.4 4.3 Tremor 4.2 7.5 Depression 3.2 5.4 Abnormal dreams 2.7 4.3 Personality disorder 2.1 <1 Psychosis 2.1 0 Abnormal gait 1.6 1.6 Akathisia 1.6 0 Extrapyramidal syndrome 1.6 1.1 Incoordination 1.6 <1 Paresthesia 1.6 3.2 Akinesia 1.1 1.1 Hypertonia 1.1 0 Neuralgia 1.1 <1 Speech disorder 1.1 1.6 Respiratory System Rhinitis 12.2 5.4 Dyspnea 4.8 1.1 Epistaxis 1.6 <1 Hiccup 1.1 0 Skin and Appendages Rash 3.2 2.1 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 10 Sweating 2.1 2.7 Special Senses Abnormal vision 5.8 5.4 Diplopia 2.1 0 Taste perversion 1.6 0 Eye disorder 1.1 0 Urogenital System Urinary frequency 2.7 6.4 Urinary tract infection 2.7 3.7 Hematuria 1.1 <1 * Events reported by at least 1% of patients receiving pergolide mesylate are included. Events Observed During the Premarketing Evaluation of Permax — This section reports event frequencies evaluated as of October 1988 for adverse events occurring in a group of approximately 1800 patients who took multiple doses of pergolide mesylate. The conditions and duration of exposure to pergolide mesylate varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. In the absence of appropriate controls in some of the studies, a causal relationship between these events and treatment with pergolide mesylate cannot be determined. The following enumeration by organ system describes events in terms of their relative frequency of reporting in the data base. Events of major clinical importance are also described in the Warnings and Precautions sections. The following definitions of frequency are used: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent: headache, asthenia, accidental injury, pain, abdominal pain, chest pain, back pain, flu syndrome, neck pain, fever; Infrequent: facial edema, chills, enlarged abdomen, malaise, neoplasm, hernia, pelvic pain, sepsis, cellulitis, moniliasis, abscess, jaw pain, hypothermia; Rare: acute abdominal syndrome, LE syndrome. Cardiovascular System — Frequent: postural hypotension, syncope, hypertension, palpitations, vasodilatations, congestive heart failure; Infrequent: myocardial infarction, tachycardia, heart arrest, abnormal electrocardiogram, angina pectoris, thrombophlebitis, bradycardia, ventricular extrasystoles, cerebrovascular accident, ventricular tachycardia, cerebral ischemia, atrial fibrillation, varicose vein, pulmonary embolus, AV block, shock; Rare: vasculitis, pulmonary hypertension, pericarditis, migraine, heart block, cerebral hemorrhage. Digestive System — Frequent: nausea, vomiting, dyspepsia, diarrhea, constipation, dry mouth, dysphagia; Infrequent: flatulence, abnormal liver function tests, increased appetite, salivary gland enlargement, thirst, gastroenteritis, gastritis, periodontal abscess, intestinal obstruction, nausea and vomiting, gingivitis, esophagitis, cholelithiasis, tooth caries, hepatitis, stomach ulcer, melena, hepatomegaly, hematemesis, eructation; Rare: sialadenitis, peptic ulcer, pancreatitis, jaundice, glossitis, fecal incontinence, duodenitis, colitis, cholecystitis, aphthous stomatitis, esophageal ulcer. Endocrine System — Infrequent: hypothyroidism, adenoma, diabetes mellitus, ADH inappropriate; Rare: endocrine disorder, thyroid adenoma. Hemic and Lymphatic System — Frequent: anemia; Infrequent: leukopenia, lymphadenopathy, leukocytosis, thrombocytopenia, petechia, megaloblastic anemia, cyanosis; This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 11 Rare: purpura, lymphocytosis, eosinophilia, thrombocythemia, acute lymphoblastic leukemia, polycythemia, splenomegaly. Metabolic and Nutritional System — Frequent: peripheral edema, weight loss, weight gain; Infrequent: dehydration, hypokalemia, hypoglycemia, iron deficiency anemia, hyperglycemia, gout, hypercholesteremia; Rare: electrolyte imbalance, cachexia, acidosis, hyperuricemia. Musculoskeletal System — Frequent: twitching, myalgia, arthralgia; Infrequent: bone pain, tenosynovitis, myositis, bone sarcoma, arthritis; Rare: osteoporosis, muscle atrophy, osteomyelitis. Nervous System — Frequent: dyskinesia, dizziness, hallucinations, confusion, somnolence, insomnia, dystonia, paresthesia, depression, anxiety, tremor, akinesia, extrapyramidal syndrome, abnormal gait, abnormal dreams, incoordination, psychosis, personality disorder, nervousness, choreoathetosis, amnesia, paranoid reaction, abnormal thinking; Infrequent: akathisia, neuropathy, neuralgia, hypertonia, delusions, convulsion, libido increased, euphoria, emotional lability, libido decreased, vertigo, myoclonus, coma, apathy, paralysis, neurosis, hyperkinesia, ataxia, acute brain syndrome, torticollis, meningitis, manic reaction, hypokinesia, hostility, agitation, hypotonia; Rare: stupor, neuritis, intracranial hypertension, hemiplegia, facial paralysis, brain edema, myelitis, hallucinations and confusion after abrupt discontinuation. Respiratory System — Frequent: rhinitis, dyspnea, pneumonia, pharyngitis, cough increased; Infrequent: epistaxis, hiccup, sinusitis, bronchitis, voice alteration, hemoptysis, asthma, lung edema, pleural effusion, laryngitis, emphysema, apnea, hyperventilation; Rare: pneumothorax, lung fibrosis, larynx edema, hypoxia, hypoventilation, hemothorax, carcinoma of lung. Skin and Appendages System — Frequent: sweating, rash; Infrequent: skin discoloration, pruritus, acne, skin ulcer, alopecia, dry skin, skin carcinoma, seborrhea, hirsutism, herpes simplex, eczema, fungal dermatitis, herpes zoster; Rare: vesiculobullous rash, subcutaneous nodule, skin nodule, skin benign neoplasm, lichenoid dermatitis. Special Senses System — Frequent: abnormal vision, diplopia; Infrequent: otitis media, conjunctivitis, tinnitus, deafness, taste perversion, ear pain, eye pain, glaucoma, eye hemorrhage, photophobia, visual field defect; Rare: blindness, cataract, retinal detachment, retinal vascular disorder. Urogenital System — Frequent: urinary tract infection, urinary frequency, urinary incontinence, hematuria, dysmenorrhea; Infrequent: dysuria, breast pain, menorrhagia, impotence, cystitis, urinary retention, abortion, vaginal hemorrhage, vaginitis, priapism, kidney calculus, fibrocystic breast, lactation, uterine hemorrhage, urolithiasis, salpingitis, pyuria, metrorrhagia, menopause, kidney failure, breast carcinoma, cervical carcinoma; Rare: amenorrhea, bladder carcinoma, breast engorgement, epididymitis, hypogonadism, leukorrhea, nephrosis, pyelonephritis, urethral pain, uricaciduria, withdrawal bleeding. Postintroduction Reports — Voluntary reports of adverse events temporally associated with pergolide that have been received since market introduction and which may have no causal relationship with the drug, include the following: neuroleptic malignant syndrome. OVERDOSAGE There is no clinical experience with massive overdosage. The largest overdose involved a young hospitalized adult patient who was not being treated with pergolide mesylate but who intentionally took 60 mg of the drug. He experienced vomiting, hypotension, and agitation. Another patient receiving a daily dosage of 7 mg of pergolide mesylate unintentionally took 19 mg/day for 3 days, after which his vital signs were normal but he experienced severe hallucinations. Within 36 hours of resumption of the prescribed dosage level, the hallucinations stopped. One patient unintentionally took 14 mg/day for 23 days instead of her prescribed 1.4 mg/day dosage. She experienced severe involuntary movements and tingling in her arms and legs. Another patient who inadvertently received 7 mg instead of the prescribed 0.7 mg This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 12 experienced palpitations, hypotension, and ventricular extrasystoles. The highest total daily dose (prescribed for several patients with refractory Parkinson’s disease) has exceeded 30 mg. Symptoms — Animal studies indicate that the manifestations of overdosage in man might include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation. The oral median lethal doses in mice and rats were 54 and 15 mg/kg respectively. Treatment — To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Management of overdosage may require supportive measures to maintain arterial blood pressure. Cardiac function should be monitored; an antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdose has not been assessed. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. There is no experience with dialysis or hemoperfusion, and these procedures are unlikely to be of benefit. DOSAGE AND ADMINISTRATION Administration of Permax should be initiated with a daily dosage of 0.05 mg for the first 2 days. The dosage should then be gradually increased by 0.1 or 0.15 mg/day every third day over the next 12 days of therapy. The dosage may then be increased by 0.25 mg/day every third day until an optimal therapeutic dosage is achieved. Permax is usually administered in divided doses 3 times per day. During dosage titration, the dosage of concurrent l-dopa/carbidopa may be cautiously decreased. In clinical studies, the mean therapeutic daily dosage of Permax was 3 mg/day. The average concurrent daily dosage of l-dopa/carbidopa (expressed as l-dopa) was approximately 650 mg/day. The efficacy of Permax at doses above 5 mg/day has not been systematically evaluated. HOW SUPPLIED Tablets (modified rectangle shape, scored): 0.05 mg, ivory, debossed with A 024, in bottles of 30 (UC5336) — NDC 65234-024-30 0.25 mg, green, debossed with A 025, in bottles of 100 (UC5337) — NDC 65234-025-10 1 mg, pink, debossed with A 026, in bottles of 100 (UC5338) — NDC 65234-026-10 _________________ Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. PERMAX is a registered trademark of Eli Lilly and Company, and licensed in the US to Amarin Pharmaceuticals, Inc. Literature revised This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-385 /S-030/ S-031/ S-035 Page 13 Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA Distributed by: Amarin Pharmaceuticals, Inc. Mill Valley, CA 94941 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:23.930729	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19385slr030,031,035_permax_lbl.pdf', 'application_number': 19385, 'submission_type': 'SUPPL ', 'submission_number': 31}
11,499	NDA 19-404/S-020 Page 3 OCUFEN (flurbiprofen sodium ophthalmic solution, USP) 0.03% Sterile DESCRIPTION OCUFEN (flurbiprofen sodium ophthalmic solution, USP) 0.03% is a sterile topical nonsteroidal anti-inflammatory product for ophthalmic use. Contains: Active: flurbiprofen sodium 0.03% (0.3 mg/mL). Preservative: thimerosal 0.005%. Inactives: citric acid; edetate disodium; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; and sodium citrate. May also contain hydrochloric acid and/or sodium hydroxide to adjust the pH. The pH of OCUFEN ophthalmic solution is 6.0 to 7.0. It has an osmolality of 260-330 mOsm/kg. CLINICAL PHARMACOLOGY Flurbiprofen sodium is one of a series of phenylalkanoic acids that have shown analgesic, antipyretic, and anti-inflammatory activity in animal inflammatory diseases. Its mechanism of action is believed to be through inhibition of the cyclo-oxygenase enzyme that is essential in the biosynthesis of prostaglandins. Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed on animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilatation, increased vascular permeability, leukocytosis, and increased intraocular pressure. Prostaglandins also appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In clinical studies, OCUFEN has been shown to inhibit the miosis induced during the course of cataract surgery. Results from clinical studies indicate that flurbiprofen sodium has no significant effect upon intraocular pressure. INDICATIONS AND USAGE OCUFEN ophthalmic solution is indicated for the inhibition of intraoperative miosis. CONTRAINDICATIONS OCUFEN ophthalmic solution is contraindicated in individuals who are hypersensitive to any components of the medication. Chemical Name: Sodium (±)-2-(2-fluoro- 4-biphenylyl)-propionate dihydrate. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-404/S-020 Page 4 WARNINGS With nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding due to interference with thrombocyte aggregation. There have been reports that OCUFEN ophthalmic solution may cause increased bleeding of ocular tissues including hyphemas in conjunction with ocular surgery. There exists the potential for cross-sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs. PRECAUTIONS General: Wound healing may be delayed with the use of OCUFEN (flurbiprofen sodium ophthalmic solution, USP) 0.03%. It is recommended that OCUFEN ophthalmic solution be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. Drug interactions: Interaction of OCUFEN ophthalmic solution with other topical ophthalmic medications has not been fully investigated. Although clinical studies with acetylcholine chloride and animal studies with acetylcholine chloride or carbachol revealed no interference, and there is no known pharmacological basis for an interaction, there have been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with OCUFEN ophthalmic solution. Carcinogenesis, Mutagenesis, Impairment of fertility: Long-term studies in mice and/or rats have shown no evidence of carcinogenicity with flurbiprofen. Long-term mutagenicity studies in animals have not been performed. Pregnancy: Pregnancy category C. Flurbiprofen has been shown to be embryocidal, delay parturition, prolong gestation, reduce weight, and/or slightly retard growth of fetuses when given to rats in daily oral doses of 0.4 mg/kg (approximately 333 times the human daily topical dose) and above. Nursing mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from flurbiprofen sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use: Safety and effectiveness in pediatric patients have not been established. Geriatric use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS Transient burning and stinging upon instillation and other minor symptoms of ocular irritation have been reported with the use of OCUFEN ophthalmic solution. Other adverse reactions reported with the use of OCUFEN ophthalmic solution include: fibrosis, miosis, and mydriasis. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-404/S-020 Page 5 Increased bleeding tendency of ocular tissues in conjunction with ocular surgery has also been reported. OVERDOSAGE Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute. DOSAGE AND ADMINISTRATION A total of four (4) drops of OCUFEN ophthalmic solution should be administered by instilling one (1) drop approximately every 1/2 hour beginning 2 hours before surgery. HOW SUPPLIED OCUFEN (flurbiprofen sodium ophthalmic solution, USP) is available for topical ophthalmic administration as a 0.03% sterile solution, and is supplied in a white opaque low density polyethylene bottle with a controlled dropper tip and a gray high impact polystyrene cap in the following size: 2.5 mL in 6 mL bottle - NDC 11980-801-03 Note: Store between 15° – 25° C (59° – 79° F). Rx only Revised February 2003  2003 Allergan, Inc. Irvine, California 92612, U.S.A 5827X  Marks owned by Allergan, Inc This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.101396	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19404scp020_ocufen_lbl.pdf', 'application_number': 19404, 'submission_type': 'SUPPL ', 'submission_number': 20}
11,501	CardioGen-82 PI to FDA_July-27-2010_CLEAN.doc HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CARDIOGEN-82 safely and effectively. See full prescribing information for CARDIOGEN-82. CARDIOGEN-82® (rubidium Rb 82 Generator) To produce rubidium Rb 82 chloride injection for intravenous use Initial U.S. Approval: 1989 -----------------------RECENT MAJOR CHANGES------------------ Indications and Usage: (1) 07/2010 Warnings and Precautions: (5.2) 07/2010 -----------------------INDICATIONS AND USAGE-------------------- CardioGen-82® is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. Rubidium Rb 82 chloride injection is a radioactive diagnostic agent indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. (1) -------------------DOSAGE AND ADMINISTRATION--------------- • Use CardioGen-82® with a specific infusion system. (2.6) • The usual adult (70 kg) dose of rubidium Rb 82 chloride injection is 1480 MBq (40 mCi), with a range of 1110-2220 MBq (30-60 mCi) infused intravenously at a rate of 50 mL/minute, not to exceed a total volume of 100 mL. Do not exceed a single dose of 2220 MBq (60 mCi). (2.3) • Start imaging acquisition 60-90 seconds after completion of the infusion; if a longer circulation time is anticipated, wait for 120 seconds. Image acquisition is typically 5 minutes long. • To obtain rest and stress images, wait 10 minutes after completion of the rest image acquisition then administer the pharmacologic stress agent in accordance with its prescribing information. Three minutes after administration of the pharmacologic stress agent, infuse the second dose of rubidium Rb 82 chloride and complete the stress image acquisition. (2.3) -------------------DOSAGE FORMS AND STRENGTHS--------------- CardioGen-82® consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time.(3) --------------------CONTRAINDICATIONS------------------ None (4) -------------WARNINGS AND PRECAUTIONS------------- • Rubidium Rb 82 chloride contributes to the cumulative radiation exposure, with the long term risks for cancer. Use the lowest dose necessary for imaging and ensure safe handling to protect the patient and health care worker. (5.1) • Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform testing in accordance with the pharmacologic stress agent’s prescribing information. (5.2) • Circulatory volume overload may result from administration of rubidium chloride injection to patients with congestive heart failure. Observe these patients for several hours following injection. (5.3) --------------------ADVERSE REACTIONS------------------ Clinical trials and post-marketing experience have identified no adverse reactions to rubidium Rb 82 chloride injection. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc at 1-800-257-8151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------DRUG INTERACTIONS-------------------- • Specific drug-drug interactions have not been studied. (7) ------------USE IN SPECIFIC POPULATIONS------------- • Pregnancy: No human or animal studies have been performed. (8.1) • Nursing Mothers: Caution should be exercised when administered to a nursing mother. (8.3) • Pediatric Use: Safety and effectiveness in pediatric patients have not been established. (8.4) See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2010 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Use Lowest Dose Necessary for Cardiac Visualization 2.2 Infusion System 2.3 Rubidium Rb 82 Chloride Injection Dosage 2.4 Radiation Dosimetry 2.5 Drug Handling 2.6 Directions for Eluting Rubidium Rb 82 Chloride Injection 2.7 Assay for Rubidium Rb 82 and Measurement of Sr-82 and Sr-85 Breakthrough 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Radiation Risks 5.2 Risks Associated with Pharmacologic Stress 5.3 Volume Overload 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal and/or Hepatic Impairment 11 DESCRIPTION 11.1 Chemical Characteristics 11.2 Physical Characteristics 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Disposal 16.3 Storage 16.4 Expiration Date 17 PATIENT COUNSELING INFORMATION 17.1 Women of Childbearing Potential 17.2 Post-study Breastfeeding Avoidance 17.3 Post-study Voiding Sections or subsections omitted from the full prescribing information are not listed This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE CardioGen-82® is a closed system used to produce rubidium Rb 82 chloride injection for intravenous administration. Rubidium Rb 82 chloride injection is indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. 2 DOSAGE AND ADMINISTRATION 2.1 Use Lowest Dose Necessary for Cardiac Visualization Use the lowest dose of rubidium Rb 82 chloride injection necessary to obtain adequate cardiac visualization. A lower dose provides less patient radiation and is consistent with the achievement of the dosing goal of As Low As Reasonably Achievable (ALARA). Most procedures do not require the maximum recommended dose of rubidium Rb 82 chloride; carefully individualize the dose and consider factors such as body size, and the equipment and technique to be employed [see Warnings and Precautions (5.2)]. 2.2 Infusion System Use CardioGen-82 only with an infusion system specifically designed for use with the generator and capable of accurate measurement and delivery of doses of rubidium Rb 82 chloride injection, not to exceed a single dose of 2220 MBq (60 mCi) and a cumulative dose of 4440 MBq (120 mCi) at a rate of 50 mL/min with a maximum volume per infusion of 100 mL and a cumulative volume not to exceed 200 mL. These limitations for a single rest and stress session reflect the conditions of use under which the drug development clinical trials were conducted. Follow instructions in the Infusion System User’s Guide for the set up and intravenous infusion of rubidium chloride injection dose(s). 2.3 Rubidium Rb 82 Chloride Injection Dosage Rubidium Rb 82 chloride injection obtained from CardioGen-82 is intended only for intravenous administration using an appropriate infusion system. The usual adult (70 kg) single dose is 1480 MBq (40 mCi) with a range of 1110-2220 MBq (30-60 mCi); a single dose of 2220 MBq (60 mCi) should not be exceeded. Administer the single dose at a rate of 50 mL/minute through a catheter inserted into a large peripheral vein, not to exceed a total volume of 100 mL. Two single doses are used to complete a rest and stress imaging session, as follows: For rest imaging • Administer a single (“resting”) rubidium Rb 82 chloride dose as described above. • Start imaging 60-90 seconds after completion of the infusion of rubidium chloride injection; if a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), wait for 120 seconds. Image acquisition is typically 5 minutes long. For stress imaging • Begin the stress imaging study 10 minutes after completion of the resting dose infusion, to allow for sufficient isotope decay. • Administer a pharmacologic stress agent in accordance with its prescribing information. • After an interval of 3 minutes, infuse a single (“stress”) rubidium Rb 82 chloride dose, as described above. • Start imaging 60-90 seconds after completion of the stress dose infusion; if a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), wait for 120 seconds. Image acquisition is typically 5 minutes long. 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 Radiation Dosimetry Table 1 shows the estimated absorbed radiation doses to an average adult patient (70 kg) from an intravenous injection of a recommended dose of 2220 MBq (60 mCi) of rubidium Rb 82 chloride. TABLE 1 Adult Absorbed Radiation Doses Organ mGy/2220 MBq rads/60 mCi Adrenals 2.15 0.22 Stomach 1.91 0.19 Small Intestine 3.11 0.32 Upper Large Intestine 1.91 0.19 Lower Large Intestine 1.91 0.19 Heart Wall 4.22 0.42 Kidneys 19.1 1.92 Liver 1.91 0.19 Lungs 3.77 0.38 Ovaries 0.84 0.084 Pancreas 1.38 0.14 Trabecular Bone 0.0055 0.00055 Cortical Bone 0.0091 0.0009 Red Marrow 0.84 0.084 Testes 0.67 0.066 Total Body 0.95 0.096 Calculated by the Internal Dosimetry Center at Oak Ridge Associated Universities based on data collected by Ryan et al. in two human subjects1 and on rat data of Kearfott2 Contaminant levels of Sr-82 and Sr-85 assumed to be 10-7 and 2.5 X 10-7 relative to Rb-82. For strontium, assumed distribution and retention: Bone 50% tb = ∞ (uniformity distributed throughout volume) Testes 0.5% tb = 1.5 day Remainder 49.5% tb = 1.5 day 2.5 Drug Handling • Limit the use of radiopharmaceuticals to physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. • Wear waterproof gloves and effective shielding when handling rubidium Rb 82 chloride injection and the infusion system. • Observe aseptic techniques in all drug handling. • Use only additive-free Sodium Chloride Injection USP to elute the generator. • Visually inspect the drug for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer eluate from the generator if there is any evidence of foreign matter. 2.6 Directions for Eluting Rubidium Rb 82 Chloride Injection Assay the eluate for rubidium Rb 82 and strontium Sr-82 and Sr-85 breakthrough each day the generator is used [see Dosage and Administration (2.7)]. Use of CardioGen-82 requires an appropriate infusion system. Consult the Infusion System User’s Guide for detailed directions on generator hookup, elution, and patient administration. Prior to use with patients, 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda establish a thorough understanding of the use and performance of the system. Consult the applicable User’s Guide for the infusion system before beginning elution. When eluting the CardioGen-82 generator: • Wear waterproof gloves during the preparation and elution processes. • Employ aseptic techniques throughout the preparation and elution processes. • Allow at least 10 minutes between elutions for regeneration of Rb-82. • Elute with additive-free Sodium Chloride Injection USP only. • Discard the first 50 mL eluate each day the generator is eluted. Employ proper safety precautions since the eluate contains radioactivity. 2.7 Assay for Rubidium Rb 82 and Measurement of Sr-82 and Sr-85 Breakthrough Determine the eluate rubidium Rb 82 content and strontium Sr 82 and strontium Sr 85 breakthrough using an ionization chamber-type dose calibrator. Perform procedure 1 through 11 below daily prior to the administration of rubidium Rb 82 chloride injection to any patients. Assay the eluate for rubidium Rb 82 as follows: 1. Set a dose calibrator for Rb-82 as recommended by the manufacturer or use the Co-60 setting and divide the reading obtained by 0.548. Obtain the reading from the instrument in millicuries. 2. Aseptically elute the generator with 50 mL of Sodium Chloride Injection USP and discard the eluate (first elution). 3. After allowing at least 10 minutes for the regeneration of Rb-82, aseptically elute the generator with 50 mL of Sodium Chloride Injection USP at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not suitable). Note the exact time of end of elution (E.O.E.). 4. Using the dose calibrator, determine the activity of Rb 82 and note the time of the reading. Correct the reading for decay to the E.O.E. using the appropriate decay factor for Rb 82 (see Table 6). Note: If the reading is taken 2 1/2 minutes after E.O.E., multiply the dose calibrator reading by 4 to correct for decay. Measure the Sr-82 breakthrough in the eluate as follows: 5. Using the sample obtained for the Rb-82 activity determination, allow the sample to stand for at least one hour to allow for the complete decay of Rb-82. 6. Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb-82 and/or Sr-82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548. Obtain the reading from the instrument in microcuries. 7. Calculate the ratio (R) of Sr-85/Sr-82 on the date of measurement using the Sr-85/Sr-82 ratio chart below (Table 2) and the ratio of Sr-85/Sr-82 on the day of calibration provided on the generator label. Determine R using the following equation: [Sr-85] R = ———— on calibration date x ratio factor on the date of measurement [Sr-82] 8. Use a correction factor (F) of 0.478 to compensate for the contribution of Sr-85 to the reading. 9. Calculate the amount of Sr-82 in the sample using the following equation: dose calibration reading (μCi) Sr-82 (μCi) = ———————————————— [1 + (R) (F)] Example: dose calibrator reading (μCi) = 0.80 Sr-85/Sr-82 ratio (R) = (1.48) Correction factor (F) = 0.478 0.80 Sr-82 (μCi) = ————————— 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda [1 + (1.48)(0.478)] Sr-82 (μCi) = 0.47 10. Determine the Sr-82 breakthrough by dividing the μCi of Sr-82 by the mCi of Rb-82 at E.O.E. Example: 0.47 μCi of Sr-82 50 mCi of Rb-82 E.O.E. 0.47 μCi Sr-82 ——————— = 0.0094 = 9.4 X 10-3μCi/mCi Rb-82 50 mCi Rb-82 The Sr-82 content must not be more than 2 x 10-2μCi/mCi of Rb-82 at E.O.E. If the Sr-82 breakthrough is above specified limits, discontinue use of the generator and contact Bracco Diagnostics Inc. 11. Determine the Sr-85 breakthrough by multiplying the result obtained in step 10 by (R) Sr-85/Sr-82 ratio. Example: 9.4 x 10-3 x 1.48 = 1.4 x 10-2 μCi Sr-85/mCi Rb-82 The Sr-85 content must not be more than 0.2 μCi/mCi of Rb-82 at E.O.E. If the Sr-85 breakthrough is above specified limits, discontinue use of the generator and contact Bracco Diagnostics Inc. TABLE 2 Sr-85/Sr-82 Ratio Chart Days Ratio Factor Days Ratio Factor 0 1.00 16 1.31 1 1.02 17 1.34 2 1.03 18 1.36 3 1.05 19 1.38 4 1.07 20 1.41 5 1.09 21 1.43 6 1.11 22 1.46 7 1.13 23 1.48 8 1.15 24 1.51 9 1.17 25 1.53 10 1.19 26 1.56 11 1.21 27 1.59 12 1.23 28 1.61 13 1.25 29 1.64 14 1.27 30 1.67 15 1.29 Day of calibration DOSAGE FORMS AND STRENGTHS CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. CardioGen-82 consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time. 5 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Radiation Risks Rubidium Rb 82 chloride contributes to the cumulative radiation exposure, with the long term risks for cancer. When considering administration of rubidium Rb 82 chloride injection to women of child-bearing potential, always seek information about pregnancy and consider the radiation risks for a fetus [see Use in Specific Populations (8.1)]. Use the lowest dose necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.3, 2.4)]. Encourage voiding as soon as a study is completed and as often as possible thereafter for at least one hour. 5.2 Risks Associated with Pharmacologic Stress Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform pharmacologic stress testing in accordance with the pharmacologic stress agent’s prescribing information and only in the setting where cardiac resuscitation equipment and trained staff are readily available. 5.3 Volume Overload Use caution during infusion as patients with congestive heart failure may experience a transitory increase in circulatory volume load. Observe these patients for several hours following rubidium chloride injection administration to detect delayed hemodynamic disturbances. 6 ADVERSE REACTIONS A review of the published literature, publicly available reference sources, adverse drug reaction reporting system, and post-marketing experience reported no adverse reactions to rubidium Rb 82 chloride injection. 7 DRUG INTERACTIONS Specific drug-drug interactions have not been studied. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with rubidium Rb 82 chloride injection. It is also not known whether rubidium Rb 82 chloride injection can cause fetal harm when administered to a pregnant woman; however, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering rubidium Rb 82 chloride injection administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from rubidium Rb 82 and the gestational timing of exposure. 8.3 Nursing Mothers It is not known whether rubidium Rb 82 chloride is excreted in human milk. Due to the short half-life of rubidium Rb 82 (75 seconds) it is unlikely that the drug would be excreted in human milk during lactation. However, because many drugs are excreted in human milk, caution should be exercised when rubidium Rb 82 chloride injection is administered to nursing women. Do not resume breastfeeding until one hour after the last infusion. 8.4 Pediatric Use Rubidium Rb 82 chloride injection safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Reported clinical experience has not identified differences in safety or effectiveness between elderly and younger subjects. In elderly patients with a clinically significant decrease in cardiac function, lengthen the delay between infusion and image acquisition [see Dosage and Administration (2.3)]. Observe these patients for the possibility of fluid overload from the infusion [see Warnings and Precautions (5.3)]. 8.6 Renal and/or Hepatic Impairment Reductions in renal or hepatic function are not anticipated to alter clearance of rubidium Rb 82 chloride injection because rubidium Rb 82 decays to stable Kr-82 with a half-life of 75 seconds and Kr-82 is exhaled through the lungs. 11 DESCRIPTION 11.1 Chemical Characteristics CardioGen-82 contains accelerator-produced strontium Sr 82 adsorbed on stannic oxide in a lead-shielded column and provides a means for obtaining sterile nonpyrogenic solutions of rubidium Rb 82 chloride injection. The chemical form of rubidium 82 is 82RbCl. The amount (millicuries) of Rb-82 obtained in each elution will depend on the potency of the generator. When eluted at a rate of 50 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 microcurie of strontium Sr 82 and not more than 0.2 microcurie of strontium Sr 85 per millicurie of rubidium Rb 82 chloride injection, and not more than 1 microgram of tin per mL of eluate. 11.2 Physical Characteristics Rubidium Rb 82 decays by positron emission and associated gamma emission with a physical half-life of 75 seconds.3 Table 3 shows the annihilation photons released following positron emission which is useful for detection and imaging studies. The decay modes of Rb-82 are: 95.5% by positron emission, resulting in the production of annihilation radiation, i.e., two 511 keV gamma rays; and 4.5% by electron capture, resulting in the emission of “prompt” gamma rays of predominantly 776.5 keV. Both decay modes lead directly to the formation of stable Kr-82.4 TABLE 3 Principal Radiation Emission Data Mean Percent Mean Energy Radiation Per Disintegration (keV) Annihilation photons (2) 191.01 511 (each) Gamma rays 13-15 776.5 The specific gamma ray constant for Rb-82 is 6.1 R/hour-millicurie at 1 centimeter. The first half-value layer is 0.7 centimeter of lead (Pb). Table 4 shows a range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb. For example, the use of a 7.0 centimeter thickness of Pb will attenuate the radiation emitted by a factor of about 1,000. TABLE 4 Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Attenuation Factor 0.7 0.5 10 -1 2.3 4.7 10-2 7.0 10-3 9.3 10-4 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Strontium Sr 82 (half-life of 25 days (600 hrs)) decays to rubidium Rb 82. To correct for physical decay of strontium Sr 82, Table 5 shows the fractions that remain at selected intervals after the time of calibration. TABLE 5 Physical Decay Chart: Sr-82 half-life 25 days Days Fraction Days Fraction Days Fraction Remaining Remaining Remaining 0 1.000 11 0.737 21 0.559 1 0.973 12 0.717 22 0.543 2 0.946 13 0.697 23 0.529 3 0.920 14 0.678 24 0.514 4 0.895 15 0.660 25 0.500 5 0.871 16 0.642 26 0.486 6 0.847 17 0.624 27 0.473 7 0.824 18 0.607 28 0.460 8 0.801 19 0.591 29 0.448 9 0.779 20 0.574 30 0.435 10 0.758 Calibration time To correct for physical decay of rubidium Rb 82, Table 6 shows the fraction of rubidium Rb 82 remaining in all 15 second intervals up to 300 seconds after time of calibration. TABLE 6 Physical Decay Chart: Rb-82 half-life 75 seconds Seconds Fraction Seconds Fraction Remaining Remaining 0 1.000 165 .218 15 .871 180 .190 30 .758 195 .165 45 .660 210 .144 60 .574 225 .125 75 .500 240 .109 90 .435 255 .095 105 .379 270 .083 120 .330 285 .072 135 .287 300 .063 150 .250 *Elution time 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rb-82 is analogous to potassium ion (K+) in its biochemical behavior and is rapidly extracted by the myocardium proportional to the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb-82 requires maintenance of ionic gradient across cell membranes. Rb-82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared rapidly from necrotic or infarcted tissue. 12.2 Pharmacodynamics 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In human studies, myocardial activity was noted within the first minute after peripheral intravenous injection of Rb-82. When areas of infarction or ischemia are present in the myocardium, they are visualized within 2-7 minutes after injection as photon-deficient, or “cold”, areas on the myocardial scan. In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and Administration (2.3)]. Blood flow brings Rb-82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen and lungs. 12.3 Pharmacokinetics With a physical half-life of 75 seconds, Rb-82 is very rapidly converted by radioactive decay into a trace amount of stable Kr-82 gas, which is passively expired by the lungs. Renal and hepatic excretion is not anticipated to play an essential role in Rb-82 elimination, although some of the Rb-82 dose may be excreted in the urine prior to radioactive decay. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine whether rubidium Rb 82 chloride injection may affect fertility in males or females. 14 CLINICAL STUDIES In a descriptive, prospective, blinded image interpretation study5 of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with ammonia N 13 (n = 111) or rubidium 82 (n = 82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary angiography. PET perfusion defects at rest and stress for seven cardiac regions (anterior, apical, anteroseptal, posteroseptal, anterolateral, posterolateral, and inferior walls) were graded on a scale of 0 (normal) to 5 (severe). Values for stenosis flow reserve, defined as flow at maximum coronary vasodilatation relative to rest flow, ranged from 0 (total occlusion) to 5 (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. A PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3). A systematic review of published literature was conducted using pre-defined inclusion/exclusion criteria which resulted in identification of 10 studies evaluating the use of Rb 82 PET myocardial perfusion imaging (MPI) for the identification of coronary artery disease as defined by catheter-based angiography. In these studies, the patient was the unit of analysis and 50% stenosis was the threshold for clinically significant coronary artery disease (CAD). Of these 10 studies, 9 studies were included in a meta-analysis for sensitivity (excluding one study with 100% sensitivity) and 7 studies were included in a meta-analysis of specificity (excluding 3 studies with 100% specificity). A random effects model yielded overall estimates of sensitivity and specificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%), respectively. The use of meta-analysis in establishing performance characteristics is limited, particularly by the possibility of publication bias (positive results being more likely to be published than negative results) which is difficult to detect especially when based on a limited number of small studies. 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 15 REFERENCES 1. Ryan et al. J Nuc Med 25(5): 94. 2. Kearfott. J Nuc Med 23(12): 1128-1132. 3. Lederer, M and Shirley, V. Table of Isotopes, 7th Edition. 4. Judge, S et. al. Applied Radiation and Isotopes (1987); vol 38, no. 3: pp 185-190. 5. Demer, L.L. K.L.Gould, R.A.Goldstein, R.L.Kirkeeide, N.A.Mullani, R.W. Smalling, A.Nishikawa, and M.E.Merhige. Assessment of coronary artery disease severity by PET: Comparison with quantitative arteriography in 193 patients. Circulation 1989; 79: 825-35. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CardioGen-82® (Rubidium Rb 82 Generator) consists of strontium Sr 82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time. A lead shield surrounded by a labeled plastic container encases the generator. The container label provides complete assay data for each generator. Directions for determining the activity of rubidium Rb 82 eluted from the generator are described above [see Dosage and Administration (2.7)]. Use CardioGen-82 (Rubidium Rb 82 Generator) only with an appropriate, properly calibrated infusion system labeled for use with the generator. Receipt, transfer, handling, possession or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate. 16.2 Disposal Hospital personnel should monitor the amount of radioactivity present within the generator prior to its disposal. Do not dispose of the generator in regular refuse systems. Store and/or dispose of the generator in accordance with the conditions of NRC radioactive materials license pursuant to 10 CFR, Part 20, or equivalent conditions pursuant to Agreement State Regulation. 16.3 Storage Store the generator at 20-25oC (68-77oF) [See USP]. 16.4 Expiration Date The generator container label provides the expiration date. Due to the short half-life of Rb-82, virtually all the radioactivity in the eluate decays within 15 minutes from the end of elution. 17 PATIENT COUNSELING INFORMATION 17.1 Women of Childbearing Potential Patients should be advised to inform their physician or healthcare provider if they are pregnant or breast- feeding. 17.2 Post-study Breastfeeding Avoidance Instruct nursing patients to substitute stored breast milk or infant formula for breast milk for one hour after administration of rubidium Rb 82 chloride injection. 17.3 Post-study Voiding Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after completion of the PET scan. Manufactured by: Manufactured for Bracco Diagnostics Inc. Princeton, NJ 08543 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda by Medi-Physics, Inc., South Plainfield, NJ 07080 US Patent 7,504,646 Printed in USA 43-8200x Revised July 2010 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.293065	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019414s012lbl.pdf', 'application_number': 19414, 'submission_type': 'SUPPL ', 'submission_number': 12}
11,498	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BREVIBLOC safely and effectively. See full prescribing information for BREVIBLOC. BREVIBLOC (esmolol hydrochloride) injection, for intravenous use Initial U.S. Approval: 1986 ----------------------------INDICATIONS AND USAGE--------------------------- BREVIBLOC is a beta adrenergic blocker indicated for the short-term treatment of:  Control of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia (1.1)  Control of perioperative tachycardia and hypertension (1.2) ----------------------DOSAGE AND ADMINISTRATION-----------------------  Administer intravenously (2.1, 2.2)  Titrate using ventricular rate or blood pressure at ≥ 4-minute intervals (2.1, 2.2)  Supraventricular tachycardia (SVT) or noncompensatory sinus tachycardia (2.1) o Optional loading dose: 500 mcg per kg infused over one minute o Then 50 mcg per kg per minute for the next 4 minutes o Adjust dose as needed to a maximum of 200 mcg per kg per minute o Additional loading doses may be administered  Perioperative tachycardia and hypertension (2.2) o Loading dose: 500 mcg per kg over 1 minute for gradual control (1 mg per kg over 30 seconds for immediate control) o Then 50 mcg per kg per minute for gradual control (150 mcg per kg per minute for immediate control) adjusted to a maximum of 200 (tachycardia) or 300 (hypertension) mcg per kg per minute (2.2) ---------------------DOSAGE FORMS AND STRENGTHS----------------------  Injection: 100 mg/10 mL (10 mg/mL) in 10 mL vial (3)  Injection: 2500 mg/250 mL (10 mg/mL) in 250 mL Premixed Injection bag (3)  Injection: 2000 mg/100 mL (20 mg/mL) in 100 mL Double Strength Premixed Injection bag (3) -------------------------------CONTRAINDICATIONS-----------------------------  Severe sinus bradycardia (4)  Heart block greater than first degree (4)  Sick sinus syndrome (4)  Decompensated heart failure (4)  Cardiogenic shock (4)  Coadministration of IV cardiodepressant calcium-channel antagonists (e.g. verapamil) in close proximity to BREVIBLOC (4, 7)  Pulmonary hypertension (4)  Known hypersensitivity to esmolol (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------  Risk of hypotension, bradycardia, and cardiac failure: Reduce or discontinue use (5.1, 5.2, 5.3, 5.10)  Risk of exacerbating reactive airway disease (5.5)  Diabetes mellitus: Increases the effect of hypoglycemic agents and masks hypoglycemic tachycardia (5.6)  Risk of unopposed alpha-agonism and severe hypertension in untreated pheochromocytoma (5.9)  Risk of myocardial ischemia when abruptly discontinued in patients with coronary artery disease (5.12, 5.15) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence> 10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-------------------------------  Digitalis glycosides: Risk of bradycardia (7)  Anticholinesterases: Prolongs neuromuscular blockade (7)  Antihypertensive agents: Risk of rebound hypertension (7)  Sympathomimetic drugs: Dose adjustment needed (7)  Vasoconstrictive and positive inotropic effect substances: Avoid concomitant use (7) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2012 FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS 1 INDICATIONS AND USAGE 6.1 Clinical Trials Experience 1.1 Supraventricular Tachycardia or Noncompensatory Sinus 6.2 Post-Marketing Experience Tachycardia 7 DRUG INTERACTIONS 1.2 Intraoperative and Postoperative Tachycardia and Hypertension 8 USE IN SPECIFIC POPULATIONS 2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy 2.1 Dosing for the Treatment of Supraventricular Tachycardia or 8.2 Labor and Delivery Noncompensatory Sinus Tachycardia 8.3 Nursing Mothers 2.2 Intraoperative and Postoperative Tachycardia and Hypertension 8.4 Pediatric Use 2.3 Transition from BREVIBLOC Therapy to Alternative Drugs 8.5 Geriatric Use 2.4 Directions for Use 8.6 Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 8.7 Renal Impairment 4 CONTRAINDICATIONS 10 OVERDOSAGE 5 WARNINGS AND PRECAUTIONS 10.1 Signs and Symptoms of Overdose 5.1 Hypotension 10.2 Treatment Recommendations 5.2 Bradycardia 10.3 Dilution Errors 5.3 Cardiac Failure 11 DESCRIPTION 5.4 Intraoperative and Postoperative Tachycardia and Hypertension 11.1 BREVIBLOC Dosage Forms 5.5 Reactive Airways Disease 12 CLINICAL PHARMACOLOGY 5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia 12.1 Mechanism of Action 5.7 Infusion Site Reactions 12.2 Pharmacodynamics 5.8 Use in Patients with Prinzmetal’s Angina 12.3 Pharmacokinetics 5.9 Use in Patients with Pheochromocytoma 13 NONCLINICAL TOXICOLOGY 5.10 Use in Hypovolemic Patients 14 CLINICAL STUDIES 5.11 Use in Patients with Peripheral Circulatory Disorders 16 HOW SUPPLIED/STORAGE AND HANDLING 5.12 Abrupt Discontinuation of BREVIBLOC 16.1 How Supplied 5.13 Hyperkalemia 16.2 Storage 5.14 Use in Patients with Metabolic Acidosis 17 PATIENT COUNSELING INFORMATION 5.15 Use in Patients with Hyperthyroidism 5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions Sections or subsections omitted from the Full Prescribing Information are not listed Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia BREVIBLOC (Esmolol Hydrochloride) is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. BREVIBLOC is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. BREVIBLOC is intended for short- term use. 1.2 Intraoperative and Postoperative Tachycardia and Hypertension BREVIBLOC (Esmolol Hydrochloride) is indicated for the short-term treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated. Use of BREVIBLOC to prevent such events is not recommended. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia Brevibloc is administered by continuous intravenous infusion with or without a loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response. Table 1 Step-Wise Dosing Step Action 1 Optional loading dose (500 mcg per kg over 1 minute), then 50 mcg per kg per min for 4 min 2 Optional loading dose if necessary, then 100 mcg per kg per min for 4 min 3 Optional loading dose if necessary, then 150 mcg per kg per min for 4 min 4 If necessary increase dose to 200 mcg per kg per min In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate. Dosages greater than 200 mcg per kg per minute provide little added heart-rate lowering effect, and the rate of adverse reactions increases. Maintenance infusions may be continued for up to 48 hours. 2.2 Intraoperative and Postoperative Tachycardia and Hypertension In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control. Immediate Control  Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary.  Adjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below. Gradual Control  Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes.  Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia (refer to Figure 1). Refer to Maximum Recommended Doses below. Maximum Recommended Doses  For the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases.  For the treatment of hypertension, higher maintenance infusion dosages (250-300 mcg per kg per min) may be required. The safety of doses above 300 mcg per kg per minute has not been studied. 2.3 Transition from BREVIBLOC Therapy to Alternative Drugs After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda When transitioning from BREVIBLOC to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of BREVIBLOC as follows: 1. Thirty minutes following the first dose of the alternative drug, reduce the BREVIBLOC infusion rate by one-half (50%). 2. After administration of the second dose of the alternative drug, monitor the patient's response, and, if satisfactory control is maintained for the first hour, discontinue the BREVIBLOC infusion. 2.4 Directions for Use BREVIBLOC is available in a pre-mixed bag and ready-to-use vial. BREVIBLOC is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Premixed Bag  The medication port is to be used solely for withdrawing an initial bolus from the bag.  Use aseptic technique when withdrawing the bolus dose.  Do not add any additional medications to the bag. usage illustration Ready-to-Use Vial The Ready-to-use Vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2)]. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Compatibility with Commonly Used Intravenous Fluids BREVIBLOC was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg Esmolol Hydrochloride per mL. BREVIBLOC was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:  Dextrose (5%) Injection, USP  Dextrose (5%) in Lactated Ringer’s Injection  Dextrose (5%) in Ringer’s Injection  Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP  Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP  Lactated Ringer’s Injection, USP  Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP  Sodium Chloride (0.45%) Injection, USP  Sodium Chloride (0.9%) Injection, USP 3 DOSAGE FORMS AND STRENGTHS All BREVIBLOC dosage forms are iso-osmotic solutions of Esmolol Hydrochloride in Sodium Chloride. Table 1 BREVIBLOC Presentations Product Name BREVIBLOC PREMIXED INJECTION (Esmolol Hydrochloride) BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION (Esmolol Hydrochloride) BREVIBLOC INJECTION (Esmolol Hydrochloride) Total Dose 2500 mg / 250 mL 2000 mg / 100 mL 100 mg / 10 mL Esmolol Hydrochloride Concentration 10 mg/mL 20 mg/mL 10 mg/mL Packaging 250 mL Bag 100 mL Bag 10 mL Vial 4 CONTRAINDICATIONS BREVIBLOC (Esmolol Hydrochloride) is contraindicated in patients with: Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Severe sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].  Heart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].  Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].  Decompensated heart failure: May worsen heart failure.  Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.  IV administration of cardiodepressant calcium-channel antagonists (e.g.,verapamil) and BREVIBLOC in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving BREVIBLOC and intravenous verapamil.  Pulmonary hypertension: May precipitate cardiorespiratory compromise.  Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible). 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. For control of ventricular heart rate, maintenance doses greater than 200 mcg per kg per min are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop BREVIBLOC. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes. 5.2 Bradycardia Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of BREVIBLOC. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving BREVIBLOC [see Contraindications (4)]. If severe bradycardia develops, reduce or stop BREVIBLOC. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.3 Cardiac Failure Beta blockers, like BREVIBLOC, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop BREVIBLOC and start supportive therapy [see Overdosage (10)]. 5.4 Intraoperative and Postoperative Tachycardia and Hypertension Monitor vital signs closely and titrate BREVIBLOC slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia. 5.5 Reactive Airways Disease Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate BREVIBLOC to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta2 stimulating agent may be administered with appropriate monitoring of ventricular rate. 5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia In patients with hypoglycemia, or diabetic patients (especially those with labile diabetes) who are receiving insulin or other hypoglycemic agents, beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be masked. Concomitant use of beta blockers and antidiabetic agents can enhance the effect of antidiabetic agents (blood glucose–lowering). 5.7 Infusion Site Reactions Infusion site reactions have occurred with the use of BREVIBLOC. They include irritation, inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when associated with extravasation [see Adverse Reactions (6.1)]. Avoid infusions into small veins or through a butterfly catheter. If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation. 5.8 Use in Patients with Prinzmetal’s Angina Beta blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. Do not use nonselective beta blockers. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.9 Use in Patients with Pheochromocytoma If BREVIBLOC is used in the setting of pheochromocytoma, give it in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure from the attenuation of beta-mediated vasodilation in skeletal muscle. 5.10 Use in Hypovolemic Patients In hypovolemic patients, BREVIBLOC can attenuate reflex tachycardia and increase the risk of hypotension. 5.11 Use in Patients with Peripheral Circulatory Disorders In patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome, and peripheral occlusive vascular disease), BREVIBLOC may aggravate peripheral circulatory disorders. 5.12 Abrupt Discontinuation of BREVIBLOC Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing BREVIBLOC. Heart rate increases moderately above pre-treatment levels 30 minutes after BREVIBLOC discontinuation. 5.13 Hyperkalemia Beta blockers, including BREVIBLOC, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with BREVIBLOC. 5.14 Use in Patients with Metabolic Acidosis Beta blockers, including BREVIBLOC, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility. 5.15 Use in Patients with Hyperthyroidism Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reaction rates are based on use of BREVIBLOC (Esmolol Hydrochloride) in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.3)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where BREVIBLOC was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)]. Table 2 Clinical Trial Adverse Reactions (Frequency ≥3%) System Organ Class (SOC) Preferred MedDRA Term Frequency VASCULAR DISORDERS Hypotension Asymptomatic hypotension Symptomatic hypotension (hyperhidrosis, dizziness) 25% 12% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Infusion site reactions (inflammation and induration) 8% GASTROINTESTINAL DISORDERS Nausea 7% NERVOUS SYSTEM DISORDERS Dizziness 3% Somnolence 3% * Hypotension resolved during BREVIBLOC (esmolol hydrochloride) infusion in 63% of patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following discontinuation of infusion. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Clinical Trial Adverse Reactions (Frequency <3%) Psychiatric Disorders Confusional state and agitation (~2%) Anxiety, depression and abnormal thinking (<1%) Nervous System Disorders Headache (~ 2%) Paresthesia, syncope, speech disorder, and lightheadedness (<1%) Convulsions (<1%), with one death Vascular Disorders Peripheral ischemia (~1%) Pallor and flushing (<1%) Gastrointestinal Disorders Vomiting (~1%) Dyspepsia, constipation, dry mouth, and abdominal discomfort have (<1%) Renal and Urinary Disorders Urinary retention (<1%) 6.2 Post-Marketing Experience In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. Cardiac Disorders Cardiac arrest, Coronary arteriospasm Skin and Subcutaneous Tissue Disorders Angioedema, Urticaria, Psoriasis 7 DRUG INTERACTIONS Concomitant use of BREVIBLOC with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate BREVIBLOC’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) BREVIBLOC should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:  Digitalis glycosides: Concomitant administration of digoxin and BREVIBLOC leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect BREVIBLOC pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.  Anticholinesterases: BREVIBLOC prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium.  Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clondidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.  Calcium channel antagonists: In patients with depressed myocardial infarction, use of BREVIBLOC with cardiodepressant calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.  Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of BREVIBLOC.  Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use BREVIBLOC to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well- controlled studies in pregnant women. BREVIBLOC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Teratogenicity studies in rats at intravenous dosages of esmolol hydrochloride) up to 3000 mcg/kg/min (10 times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min produced minimal maternal toxicity and increased fetal resorptions. 8.2 Labor and Delivery Although there are no adequate and well-controlled studies in pregnant women, use of esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. BREVIBLOC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BREVIBLOC, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of BREVIBLOC in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of BREVIBLOC did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment No special precautions are necessary in patients with hepatic impairment because BREVIBLOC is metabolized by red-blood cell esterases [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment is required for esmolol in patients with renal impairment receiving a maintenance infusion of esmolol 150 mcg/kg for 4 hours. There is no information on the tolerability of maintenance infusions of esmolol using rates in excess of 150 mcg/kg or maintained longer than 4 hours [see Clinical Pharmacology (12.3)]. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose Overdoses of BREVIBLOC (Esmolol Hydrochloride) can cause cardiac and central nervous system effects. These effects may precipitate severe signs, symptoms, sequelae, and complications (for example, severe cardiac and respiratory failure, including shock and coma), and may be fatal. Continuous monitoring of the patient is required.  Cardiac effects include bradycardia, atrioventricular block (1st -, 2nd -, 3rd degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity.  Central nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma.  In addition, bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia, and hypoglycemia (especially in children) may occur. 10.2 Treatment Recommendations Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the BREVIBLOC infusion. Then, based on the observed clinical effects, consider the following general measures. Bradycardia: Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing. Cardiac Failure Consider intravenous administration of a diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, or inamrinone. Glucagon has been reported to be useful. Symptomatic hypotension Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine. Bronchospasm Consider intravenous administration of a beta2 stimulating agent or a theophylline derivative. 10.3 Dilution Errors Massive accidental overdoses of BREVIBLOC have resulted from dilution errors. Use of BREVIBLOC PREMIXED INJECTION and BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION may reduce the potential for dilution errors. Some of these overdoses have been Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 g (12.5-50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of BREVIBLOC resolved. 11 DESCRIPTION BREVIBLOC (Esmolol Hydrochloride) is a beta adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol Hydrochloride is:  (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure: structural formula  Esmolol Hydrochloride has the empirical formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair.  Esmolol Hydrochloride is a white to off-white crystalline powder. It is a relatively hydrophilic compound which is very soluble in water and freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol. 11.1 BREVIBLOC Dosage Forms All BREVIBLOC presentations are clear, colorless to light yellow, sterile, nonpyrogenic, iso-osmotic solutions of esmolol hydrochloride in sodium chloride. The formulations for BREVIBLOC PREMIXED INJECTION, BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION, and BREVIBLOC INJECTION are described in the table below: Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 3 BREVIBLOC Formulations BREVIBLOC PREMIXED INJECTION (Esmolol Hydrochloride) BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION (Esmolol Hydrochloride) BREVIBLOC INJECTION (Esmolol Hydrochloride) Esmolol Hydrochloride 10 mg/mL 20 mg/mL 10 mg/mL Sodium Chloride, USP 5.9 mg/mL 4.1 mg/mL 5.9 mg/mL Water for Injection, USP Q.S. to volume of 250 mL Q.S. to volume of 100 mL Q.S. to volume of 10 mL Sodium Acetate Trihydrate , USP 2.8 mg/mL 2.8 mg/mL 2.8 mg/mL Glacial Acetic Acid, USP 0.546 mg/mL 0.546 mg/mL 0.546 mg/mL Sodium Hydroxide Q.S. to adjust pH to 4.5-5.5 Hydrochloric Acid Q.S. to adjust pH to 4.5-5.5 Q.S. = Quantity sufficient The calculated osmolarity of BREVIBLOC PREMIXED INJECTION and BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION is 312 mOsmol/L. The 250 mL and 100 mL bags are non-latex, non-PVC IntraVia bags with dual PVC ports. The IntraVia bags are manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical compounds from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action BREVIBLOC (Esmolol Hydrochloride) is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. BREVIBLOC inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12.2 Pharmacodynamics Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of BREVIBLOC, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of BREVIBLOC have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exihibits negligible pharmacological activity. In human electrophysiology studies, BREVIBLOC produced effects typical of a beta blocker; a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length. In patients undergoing radionuclide angiography, BREVIBLOC, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, BREVIBLOC produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but BREVIBLOC produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of BREVIBLOC produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of BREVIBLOC infusion, all of the hemodynamic parameters had returned to pretreatment levels. The relative cardioselectivity of BREVIBLOC was demonstrated in 10 mildly asthmatic patients. Infusions of BREVIBLOC 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, BREVIBLOC produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and BREVIBLOC was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of BREVIBLOC for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients). 12.3 Pharmacokinetics Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. Using an appropriate loading dose, steady-state blood levels of BREVIBLOC for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion. Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage. Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity, and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. After a 4 hours maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of BREVIBLOC, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD. Methanol blood levels, monitored in subjects receiving BREVIBLOC for up to 6 hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity. BREVIBLOC has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound. 13 NONCLINICAL TOXICOLOGY Because of its short term usage no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol. 14 CLINICAL STUDIES Supraventricular Tachycardia In two multicenter, randomized, double-blind, controlled comparisons of BREVIBLOC with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of BREVIBLOC were Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with BREVIBLOC developed either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at a dosage of 200 mcg/kg/min or less. The average effective dosage of BREVIBLOC was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the BREVIBLOC and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients. In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with BREVIBLOC (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with BREVIBLOC. For both BREVIBLOC and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied BREVIBLOC PREMIXED INJECTION  NDC 10019-055-61, 2500 mg / 250 mL (10 mg/mL) Ready-to-use IntraVia Bags BREVIBLOC DOUBLE STRENGTH PREMIXED INJECTION  NDC 10019-075-87, 2000 mg / 100 mL (20 mg/mL) Ready-to-use IntraVia Bags BREVIBLOC INJECTION  NDC 10019-115-01, 100 mg / 10 mL (10 mg/mL) Ready-to-use Vials, Package of 25 16.2 Storage Store at 25˚C (77˚F). Excursions permitted to 15˚-30˚C (59˚-86˚F). [See USP Controlled Room Temperature.] Protect from freezing. Avoid excessive heat. Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded. Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact. Preparation for intravenous administration:  Use aseptic technique.  Suspend premixed bag from eyelet support.  Remove plastic protector from delivery port at bottom of bag.  Attach administration set.  Refer to complete directions accompanying set. 17 PATIENT COUNSELING INFORMATION Physicians should inform patients of the risks associated with BREVIBLOC:  The most common adverse reactions are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension. company logo Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA Baxter, Brevibloc, Brevibloc Premixed and IntraVia are trademarks of Baxter International Inc. MLT-01088/7.0 Reference ID: 3228733 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.368889	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019386s043lbl.pdf', 'application_number': 19386, 'submission_type': 'SUPPL ', 'submission_number': 43}
11,500	NDA 19-414/S-011 Page 3 NDA 19-414/S-011 Page 4 NDA 19-414/S-011 Page 5 NDA 19-414/S-011 Page 6 NDA 19-414/S-011 Page 7 NDA 19-414/S-011 Page 8 NDA 19-414/S-011 Page 9 NDA 19-414/S-011 Page 10 NDA 19-414/S-011 Page 11 NDA 19-414/S-011 Page 12 NDA 19-414/S-011 Page 13 NDA 19-414/S-011 Page 14 NDA 19-414/S-011 Page 15 NDA 19-414/S-011 Page 16 NDA 19-414/S-011 Page 17 NDA 19-414/S-011 Page 18 NDA 19-414/S-011 Page 19 NDA 19-414/S-011 Page 20 NDA 19-414/S-011 Page 21	custom-source	2025-02-12T13:45:24.409313	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019414s011lbl.pdf', 'application_number': 19414, 'submission_type': 'SUPPL ', 'submission_number': 11}
11,502	HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CARDIOGEN-82 safely and effectively. See full prescribing information for CARDIOGEN-82. CARDIOGEN-82® (rubidium Rb 82 generator) To produce rubidium Rb 82 chloride injection, for intravenous use Initial U.S. Approval: 1989 WARNING: UNINTENDED STRONTIUM-82 (Sr-82) AND STRONTIUM-85 (Sr-85) RADIATION EXPOSURE Please see full prescribing information for complete boxed warning  Unintended radiation exposure occurs when the levels of Sr-82 or Sr-85 in the rubidium Rb 82 chloride injection exceed limits. (5.1)  Perform generator eluate tests: 1) Record each eluate volume, including waste and test volumes. (2.4) 2) Determine Rb-82, Sr-82, Sr-85 levels in the eluate:  Once daily, prior to any drug administrations, and  With additional daily tests after detection of an Alert Limit. (2.5) 3) Stop use of the generator at its Expiration Limit. (2.6) ---------------------------RECENT MAJOR CHANGES------------------------------- Boxed Warning: Unintended radiation exposure 02/2012 Dosage and Administration: Elution, eluate testing, expiration, 02/2012 dosimetry (2.4, 2.5, 2.6, 2.7) Warnings and Precautions: Unintended radiation exposure (5.1) 02/2012 ----------------------------INDICATIONS AND USAGE-------------------------------- CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. Rubidium Rb 82 chloride injection is a radioactive diagnostic agent indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. (1) -----------------------DOSAGE AND ADMINISTRATION----------------------------  Use CardioGen-82 with a specific infusion system. (2.1)  The recommended adult (70 kg) dose of rubidium Rb 82 chloride injection is 1480 MBq (40 mCi), with a range of 1110-2220 MBq (30-60 mCi) infused intravenously at a rate of 50 mL/minute, not to exceed a total volume of 100 mL. Do not exceed a single dose of 2220 MBq (60 mCi). (2.2)  Start imaging acquisition 60-90 seconds after completion of the infusion; if a longer circulation time is anticipated, wait for 120 seconds. Image acquisition is typically 5 minutes long. (2.2)  To obtain rest and stress images, wait 10 minutes after completion of the rest image acquisition then administer the pharmacologic stress agent in accordance with its prescribing information. Three minutes after administration of the pharmacologic stress agent, infuse the second dose of rubidium Rb-82 chloride and complete the stress image acquisition. (2.2) ------------------------DOSAGE FORMS AND STRENGTHS----------------------- CardioGen-82 consists of strontium Sr-82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time. (3) ----------------------------CONTRAINDICATIONS------------------------------------- None. (4) -------------------------WARNINGS AND PRECAUTIONS----------------------------  Unintended radiation exposure occurs when Sr-82 and Sr-85 levels in rubidium Rb 82 chloride injection exceed specified generator eluate limits (5.1)  Pharmacologic induction of cardiovascular stress: May cause serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, broncho constriction, and cerebrovascular events. Perform testing only in setting where cardiac resuscitation equipment and trained staff are readily available. (5.2)  Volume overload: Observe patients with congestive heart failure during infusion and for several hours following injection. (5.3) ------------------------------ADVERSE REACTIONS------------------------------------- To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc at 1-800-257-8151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch --------------------------USE IN SPECIFIC POPULATIONS--------------------------  Pregnancy: Only administer Rb-82 if clearly needed. (8.1)  Nursing Mothers: Do not resume breast feeding until one hour after the last infusion. (8.3)  Pediatric Use: Safety and effectiveness in pediatric patients have not been established. (8.4) See 17 for PATIENT COUNSELING INFORMATION Revised: 2/2012 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: UNINTENDED Sr-82 and Sr-85 EXPOSURE 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Infusion System 2.2 Rubidium Rb 82 Chloride Injection Dosage 2.3 Drug Handling 2.4 Directions for Eluting Rubidium Rb 82 Chloride Injection 2.5 Eluate Testing Protocol 2.6 CardioGen-82 Expiration 2.7 Radiation Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Unintended Sr-82 and Sr-85 Radiation Exposure 5.2 Risks Associated with Pharmacologic Stress 5.3 Volume Overload 5.4 Cumulative Radiation Exposure: Long-Term Risk of Cancer 6 ADVERSE REACTIONS 6.1 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 11.1 Chemical Characteristics 11.2 Physical Characteristics 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Disposal 16.3 Storage 17 PATIENT COUNSELING INFORMATION 17.1 Women of Childbearing Potential 17.2 Post-study Breastfeeding Avoidance 17.3 Post-study Voiding Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3084430 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION WARNING: UNINTENDED STRONTIUM-82 (Sr-82) AND STRONTIUM-85 (Sr-85) RADIATION EXPOSURE Unintended radiation exposure occurs when the levels of Sr-82 or Sr-85 in the rubidium Rb 82 chloride injection exceed specified limits [see Warnings and Precautions (5.1)] Perform generator eluate tests: 1) Record each generator eluate volume, including waste and test volumes, and keep a record of the cumulative eluate volume [see Dosage and Administration (2.4)]. 2) Determine Rb-82, Sr-82, Sr-85 in the generator eluate:  Once a day, prior to any drug administrations, and  At additional daily tests after detection of an Alert Limit. Alert Limits are: o 14 L for the generator’s cumulative eluate volume, or o An eluate Sr-82 level of 0.002 μCi/ mCi Rb-82, or o An eluate Sr-85 level of 0.02 Sr-85 μCi/ mCi Rb-82. o Perform the additional daily tests at time points determined by the day’s elution volume; tests are performed every 750 mL [see Dosage and Administration (2.5)]. 3) Stop use of a generator at an Expiration Limit of: o 17 L for the generator’s cumulative eluate volume, or o 42 days post generator calibration date, or o An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or o An eluate Sr-85 level of 0.1 μCi /mCi Rb-82 [see Dosage and Administration (2.6)]. 1 INDICATIONS AND USAGE CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous administration. Rubidium Rb 82 chloride injection is indicated for Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult patients with suspected or existing coronary artery disease. 2 DOSAGE AND ADMINISTRATION 2.1 Infusion System Use CardioGen-82 only with an infusion system specifically designed for use with the generator and capable of accurate measurement and delivery of doses of rubidium Rb 82 chloride injection. Follow instructions in the Infusion System User’s Guide for the set up and intravenous infusion of rubidium Rb 82 chloride injection dose(s). 2.2 Rubidium Rb 82 Chloride Injection Dosage The recommended adult single dose of rubidium Rb 82 chloride injection is 1480 MBq (40 mCi) with a range of 1110-2220 MBq (30-60 mCi).  Do not exceed a single dose of 2220 MBq (60 mCi).  Use the lowest dose necessary to obtain adequate cardiac visualization consistent with the dosing goal of as low as reasonably achievable (ALARA).  Individualize the dose by considering factors such as body size, and the imaging equipment and technique.  Administer the single dose at 50 mL/minute through a catheter inserted into a large peripheral vein; do not to exceed a total infusion volume of 100 mL. Administer two separate single doses to complete rest and stress myocardial perfusion imaging as follows: For rest imaging:  Administer a single (“rest”) rubidium Rb-82 chloride dose;  Start imaging 60-90 seconds after completion of the infusion of the rest dose and acquire images for 5 minutes; if a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), start imaging 120 seconds after the rest dose. Reference ID: 3084430 2 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda For stress imaging:  Begin the study 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb-82 decay;  Administer a pharmacologic stress agent in accordance with its prescribing information;  After an interval of 3 minutes, infuse a single (“stress”) rubidium Rb-82 chloride dose;  Start imaging 60-90 seconds after completion of the stress Rb-82 chloride dose infusion and acquire images for 5 minutes; if a longer circulation time is anticipated start imaging 120 sec after the stress dose. 2.3 Drug Handling  Limit the use of radiopharmaceuticals to physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.  Wear waterproof gloves and effective shielding when handling rubidium Rb-82 chloride injection and the infusion system.  Observe aseptic techniques in all drug handling.  Use only additive-free Sodium Chloride Injection USP to elute the generator.  Visually inspect the drug for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer eluate from the generator if there is any evidence of foreign matter. 2.4 Directions for Eluting Rubidium Rb 82 Chloride Injection  Allow at least 10 minutes between elutions for regeneration of Rb-82.  Elute with additive-free Sodium Chloride Injection USP only. Additives (particularly calcium ions, to which strontium ions are chemically analogous), may cause the release of substantial amounts of Sr-82 and/or Sr-85 into the eluate regardless of the age or prior use of the generator.  Discard the first 50 mL eluate each day the generator is first eluted. Employ proper safety precautions since the eluate contains radioactivity.  Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the cumulative volume of eluate from the generator. 2.5 Eluate Testing Protocol Use additive-free sodium chloride injection USP for all elutions. Apply aseptic technique throughout. Before administering rubidium Rb 82 chloride injection to the first patient each day, perform the following test: Strontium Alert Limits and Mandatory Eluate Testing:  Use an ionization chamber-type dose calibrator for eluate testing.  Daily, before administering rubidium Rb 82 chloride injection to any patient, perform an eluate testing to determine Rb-82, Sr-82, and Sr-85 levels  Perform additional daily eluate tests after detecting any of the following Alert Limits: o 14 L total elution volume has passed through the generator column, or o Sr-82 level reaches 0.002 µCi per mCi Rb-82, or o Sr-85 level reaches 0.02 µCi per mCi Rb-82. Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed every 750 mL. o For example, if an Alert Limit were reached and the clinical site eluted less than 750 mL from the generator during the day, then no additional eluate tests would have been performed that day. o If the same clinical site the next day eluted 1,500 mL from the generator, then the site would have performed three tests that day: 1) the required daily test that precedes any patient dosing, 2) a test at the 750 mL elution point, and 3) a test at the 1,500 mL elution point. o If a generator’s Alert Limit is reached, the clinical site performs the additional daily tests (at intervals of 750 mL) each subsequent day the generator is used. The additional tests are necessary to promptly detect excessive Sr-82 and/or Sr-85 in eluates. Reference ID: 3084430 3 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rubidium Eluate Level Testing: 1. Set a dose calibrator for Rb-82 as recommended by the manufacturer or use the Co-60 setting and divide the reading obtained by 0.548. Obtain the reading from the instrument in millicuries. 2. Elute the generator with 50 mL of Sodium Chloride Injection USP and discard the eluate (first elution). 3. Allow at least 10 minutes for the regeneration of Rb-82, then elute the generator with 50 mL of Sodium Chloride Injection USP at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not suitable). Note the exact time of end of elution (E.O.E.). 4. Using the dose calibrator, determine the activity of Rb-82 and note the time of the reading. Correct the reading for decay to the E.O.E. using the appropriate decay factor for Rb-82 (see Table 1). Note: If the reading is taken 2 1/2 minutes after end of elution, multiply the dose calibrator reading by 4 to correct for decay. Strontium Eluate Level Testing: 5. Using the sample obtained for the Rb-82 activity determination, allow the sample to stand for at least one hour to allow for the complete decay of Rb-82. 6. Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb-82 and/or Sr-82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548. Set the instrument to read in microcuries and record the reading in the display. 7. Calculate the ratio (R) of Sr-85/Sr-82 on the day (postcalibration) of the measurement using the ratio of Sr 85/Sr-82 on the day of calibration provided on the generator label and the Sr-85/Sr-82 Ratio Factor from Table 2. Determine R using the following equation: [Sr-85] R = ———— on calibration date X Ratio Factor on the day (post-calibration) of measurement [Sr-82] 8. Use a correction factor (F) of 0.478 to compensate for the contribution of Sr-85 to the reading. 9. Calculate the amount of Sr-82 in the sample using the following equation: dose calibration reading (μCi) Sr-82 (μCi) = ————————————— [1 + (R) (F)] Example: dose calibrator reading (μCi) = 0.8; Sr85/Sr82 ratio (R) =1.48; correction factor (F) = 0.478. 0.8 Sr-82 (μCi) = ———————— = 0.47 [1 + (1.48)(0.478)] 10. Determine if Sr-82 in the eluate exceeds an Alert or Expiration Limit by dividing the μCi of Sr-82 by the mCi of Rb-82 at End of Elution (see below for further instructions based on the Sr-82 level) Example: 0.47 μCi of Sr-82; 50 mCi of Rb-82 E.O.E. 0.47 μCi Sr-82 ——————— = 0.0094 μCi/mCi Rb-82 (is above Alert Limit of 0.002; additional daily eluate 50 mCi Rb-82 testing must be performed) 11. Determine if Sr-85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 10 by (R) as calculated in step 7 (above). Example: 0.0094 x 1.48 = 0.014 μCi Sr-85/mCi Rb-82 (test result is below Alert and Expiration Limits) Use Table 1 to calculate the decay factor for Rb-82; step 4 (above). Reference ID: 3084430 4 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda TABLE 1 Physical Decay Chart: Rb-82 half-life 75 seconds Seconds Fraction Seconds Fraction Remaining Remaining 0 1.000 165 0.218 15 0.871 180 0.190 30 0.758 195 0.165 45 0.660 210 0.144 60 0.574 225 0.125 75 0.500 240 0.109 90 0.435 255 0.095 105 0.379 270 0.083 120 0.330 285 0.072 135 0.287 300 0.063 150 0.250 Elution time Use Table 2 to calculate the ratio (R) of Sr-85/Sr-82; step 7 (above). TABLE 2 Sr-85/Sr-82 Ratio Chart (Sr-85 T ½ = 65 days, Sr-82 ½ = 25 days) Days Ratio Factor Days Ratio Factor Days Ratio Factor 0 1.00 16 1.31 32 1.73 1 1.02 17 1.34 33 1.76 2 1.03 18 1.36 34 1.79 3 1.05 19 1.38 35 1.82 4 1.07 20 1.41 36 1.85 5 1.09 21 1.43 37 1.88 6 1.11 22 1.46 38 1.91 7 1.13 23 1.48 39 1.95 8 1.15 24 1.51 40 1.98 9 1.17 25 1.53 41 2.01 10 1.19 26 1.56 42 2.05 11 1.21 27 1.58 12 1.23 28 1.61 13 1.25 29 1.64 14 1.27 30 1.67 15 1.29 31 1.70 Day of calibration 2.6 CardioGen-82 Expiration Stop use of the CardioGen-82 generator once any one of the following Expiration Limits is reached.  A total elution volume of 17 L has passed through the generator column, or  42 days post calibration date, or  An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or  An eluate Sr-85 level of 0.1 μCi /mCi Rb-82. 2.7 Radiation Dosimetry Reference ID: 3084430 5 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda The estimated absorbed radiation doses for Rb-82, Sr-82, and Sr-85 from an intravenous injection rubidium Rb- 82 chloride are shown in Table 3. Table 3 Adult Absorbed Radiation Dose Coefficient Organa,b Rb-82 Sr-82 Sr-85 (Average for Rest and Stress) mrem/µCi mrem/µCi mrem/mCi (µSv/3.7kBq)c (µSv/3.7kBq)c (µSv/3.7 MBq)c Adrenals 7.56 10.6 5.03 Bone – Osteogenic cells 1.86 --- --- Bone Surface ---- 107 9.81 Brain 0.60 8.29 2.96 Breast 0.82 7.03 1.72 Gall Bladder Wall 3.17 8.47 2.82 Heart Wall 16.5 8.18 2.67 Kidneys 20.04 9.18 2.50 Liver 4.20 8.10 2.50 Lower Large Intestine Wall 2.84 51.8 5.14 Lungsd 10.7 8.25 2.84 Muscles 1.29 8.14 2.66 Ovaries 1.41 10.2 4.29 Pancreas 8.85 9.10 3.46 Red Marrow 1.19 91.0 9.84 Skin 1.14 7.03 1.75 Small Intestine 4.76 9.62 4.03 Spleen 6.61 8.10 2.54 Stomach 8.14 7.84 2.26 Testes 0.82 7.25 1.70 Thymus 1.49 7.84 2.33 Thyroid 6.11 8.07 2.57 Upper Large Intestine 5.94 23.7 3.62 Urinary Bladder Wall 1.61 21.9 2.90 Uterus 3.72 9.14 3.32 Total Body 1.77 Not Calculated Not Calculated Effective Dosee 4.74 f 23.4 4.03 aRb-82 doses are averages of rest and stress dosimetry data (see Senthamizhchelvan et al. 1,2). To calculate organ doses (mrem) from Rb-82, multiply the dose coefficient for each organ by the administered activity in mCi. bSr-82 and Sr-85 doses are calculated using software package DCAL and ICRP dose coefficients. To calculate organ doses (mrem) attributable to Sr-82, and Sr-85, multiply the dose coefficients by the calculated amounts of strontium in µCi.3 c To convert to SI units, insert the dose coefficient into the formula in parentheses, e.g. for adrenals 7.56 mrem/mCi = 7.56 µSv/37 MBq = 2.04 x 10-13 Sv/Bq . d Calculated from ICRP 66 e Calculated from ICRP 60 f Stress phase only Reference ID: 3084430 6 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS CardioGen-82 is a closed system used to produce rubidium Rb 82 chloride injection for intravenous use. CardioGen-82 consists of strontium Sr-82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Unintended Sr-82 and Sr-85 Exposure Unintended radiation exposure occurs when the Sr-82 and Sr-85 levels in rubidium Rb 82 chloride injections exceed the specified generator eluate limits. Unintended exposure to strontium radiation has occurred in some patients who received rubidium Rb 82 injections at clinical sites where generator eluate testing appeared insufficient. The physical half lives of Sr-82 and Sr-85 are 25 days and 65 days, respectively, in contrast to Rb-82 which has a physical half-life of 75 seconds. Unintended exposure to strontium radiation contributes to a patient’s overall cumulative radiation dose [see Warnings and Precautions (5.4)]. To minimize the risk of unintended radiation exposure, strict adherence to a daily eluate testing protocol is required. Stop using the rubidium generator when the expiration limits are reached [see Dosage and Administration (2.5) and (2.6)]. 5.2 Risks Associated with Pharmacologic Stress Pharmacologic induction of cardiovascular stress may be associated with serious adverse reactions such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform pharmacologic stress testing in accordance with the pharmacologic stress agent’s prescribing information and only in the setting where cardiac resuscitation equipment and trained staff are readily available. 5.3 Volume Overload Patients with congestive heart failure or the elderly may experience a transitory increase in circulatory volume load. Observe these patients during infusion and for several hours following rubidium chloride injection administration to detect delayed hemodynamic disturbances. 5.4 Cumulative Radiation Exposure: Long-Term Risk of Cancer Rubidium Rb 82 chloride injection, similar to other radiopharmaceuticals, contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Use the lowest dose of rubidium Rb 82 chloride injection necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.2) and (2.3)]. Encourage patients to void as soon as a study is completed and as often as possible thereafter for at least one hour. 6 ADVERSE REACTIONS 6.1 Postmarketing Experience The following serious adverse reactions have been identified during postapproval use of CardioGen-82. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 3084430 7 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Unintended radiation exposure has occurred in some patients who received rubidium Rb 82 chloride injections at clinical sites where generator eluate testing appeared insufficient [see Boxed Warning, Warnings and Precautions (5.1), and Dosage and Administration (2.5)]. 7 DRUG INTERACTIONS Specific drug-drug interactions have not been studied. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with rubidium Rb 82 chloride injection. It is also not known whether rubidium Rb 82 chloride injection can cause fetal harm when administered to a pregnant woman; however, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering rubidium Rb 82 chloride injection administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from rubidium Rb-82 and the gestational timing of exposure. Administer rubidium Rb-82 to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether rubidium Rb 82 chloride injection is excreted in human milk. Due to the short half- life of rubidium Rb-82 (75 seconds) it is unlikely that the drug would be excreted in human milk during lactation. However, because many drugs are excreted in human milk, caution should be exercised when rubidium Rb-82 chloride injection is administered to nursing women. Do not resume breastfeeding until one hour after the last infusion. 8.4 Pediatric Use Rubidium Rb 82 chloride injection safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In elderly patients with a clinically important decrease in cardiac function, lengthen the delay between infusion and image acquisition [see Dosage and Administration (2.2)]. Observe for the possibility of fluid overload [see Warnings and Precautions (5.3)]. 8.6 Renal Impairment Reductions in renal function are not anticipated to alter clearance of rubidium Rb 82 chloride injection because Rb-82 decays to stable Kr-82 with a half-life of 75 seconds and Kr-82 is exhaled through the lungs. 8.7 Hepatic Impairment Reductions in hepatic function are not anticipated to alter clearance of rubidium Rb 82 chloride injection. 11 DESCRIPTION 11.1 Chemical Characteristics CardioGen-82 contains accelerator-produced Sr-82 adsorbed on stannic oxide in a lead-shielded column and provides a means for obtaining sterile nonpyrogenic solutions of rubidium Rb 82 chloride injection. The chemical form of Rb-82 is 82RbCl. The amount (millicuries) of Rb-82 obtained in each elution will depend on the potency of the generator. When eluted at a rate of 50 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 microcurie of Sr-82 and not more than 0.2 microcurie of Sr-85 per millicurie of rubidium Rb 82 chloride injection, and not more than 1 microgram of tin per mL of eluate. 11.2 Physical Characteristics Reference ID: 3084430 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Rb-82 decays by positron emission and associated gamma emission with a physical half-life of 75 seconds.4 Table 4 shows the annihilation photons released following positron emission which are useful for detection and imaging studies. The decay modes of Rb-82 are: 95.5% by positron emission, resulting in the production of annihilation radiation, i.e., two 511 keV gamma rays; and 4.5% by electron capture, resulting in the emission of “prompt” gamma rays of predominantly 776.5 keV. Both decay modes lead directly to the formation of stable Kr-82.4 TABLE 4 Principal Radiation Emission Data Mean Percent Mean Energy Radiation Per Disintegration (keV) Annihilation photons (2) 191.01 511 (each) Gamma rays 13-15 776.5 The specific gamma ray constant for Rb-82 is 6.1 R/hour-millicurie at 1 centimeter. The first half-value layer is 0.7 centimeter of lead (Pb). Table 5 shows a range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead.5 For example, the use of a 7.0 centimeter thickness of Pb will attenuate the radiation emitted by a factor of about 1,000. TABLE 5 Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Attenuation Factor 0.7 0.5 10 -1 2.3 4.7 10-2 7.0 10-3 9.3 10-4 Sr-82 (half-life of 25 days (600 hrs)) decays to Rb-82. To correct for physical decay of Sr-82, Table 6 shows the fractions that remain at selected intervals after the time of calibration. TABLE 6 Physical Decay Chart: Sr-82 half-life 25 days Days Fraction Days Fraction Days Fraction Remaining Remaining Remaining 0 1.000 15 0.660 30 0.435 1 0.973 16 0.642 31 0.423 2 0.946 17 0.624 32 0.412 3 0.920 18 0.607 33 0.401 4 0.895 19 0.591 34 0.390 5 0.871 20 0.574 35 0.379 6 0.847 21 0.559 36 0.369 7 0.824 22 0.543 37 0.359 8 0.801 23 0.529 38 0.349 9 0.779 24 0.514 39 0.339 10 0.758 25 0.500 40 0.330 11 0.737 26 0.486 41 0.321 Reference ID: 3084430 9 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 12 0.717 27 0.473 42 0.312 13 0.697 28 0.460 14 0.678 29 0.448 Calibration time To correct for physical decay of Rb-82, Table 1 shows the fraction of Rb-82 remaining in all 15 second intervals up to 300 seconds after time of calibration [see Dosage and Administration (2.5)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rb-82 is analogous to potassium ion (K+) in its biochemical behavior and is rapidly extracted by the myocardium proportional to the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb-82 requires maintenance of ionic gradient across cell membranes. Rb-82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared rapidly from necrotic or infarcted tissue. 12.2 Pharmacodynamics In human studies, myocardial activity was noted within the first minute after peripheral intravenous injection of Rb-82. When areas of infarction or ischemia are present in the myocardium, they are visualized within 2-7 minutes after injection as photon-deficient, or “cold”, areas on the myocardial scan. In patients with reduced cardiac function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and Administration (2.2)]. Blood flow brings Rb-82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also observed in other highly vascularized organs, such as the kidneys, liver, spleen and lungs. 12.3 Pharmacokinetics With a physical half-life of 75 seconds, Rb-82 is very rapidly converted by radioactive decay into a trace amount of stable Kr-82 gas, which is passively expired by the lungs. Renal and hepatic excretion is not anticipated to play an essential role in Rb-82 elimination, although some of the Rb-82 dose may be excreted in the urine prior to radioactive decay. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine whether rubidium Rb 82 chloride injection may affect fertility in males or females. 14 CLINICAL STUDIES In a descriptive, prospective, blinded image interpretation study6 of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with ammonia N 13 (n = 111) or rubidium Rb-82 chloride (n = 82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary angiography. PET perfusion defects at rest and stress for seven cardiac regions (anterior, apical, anteroseptal, posteroseptal, anterolateral, posterolateral, and inferior walls) were graded on a scale of 0 (normal) to 5 (severe). Values for stenosis flow reserve, defined as flow at maximum coronary vasodilatation relative to rest flow, ranged from 0 (total occlusion) to 5 (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. A PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3). A systematic review of published literature was conducted using pre-defined inclusion/exclusion criteria which resulted in identification of 10 studies evaluating the use of Rb-82 PET myocardial perfusion Reference ID: 3084430 10 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda imaging (MPI) for the identification of coronary artery disease as defined by catheter-based angiography. In these studies, the patient was the unit of analysis and 50% stenosis was the threshold for clinically significant coronary artery disease (CAD). Of these 10 studies, 9 studies were included in a meta-analysis for sensitivity (excluding one study with 100% sensitivity) and 7 studies were included in a meta-analysis of specificity (excluding 3 studies with 100% specificity). A random effects model yielded overall estimates of sensitivity and specificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%), respectively. The use of meta-analysis in establishing performance characteristics is limited, particularly by the possibility of publication bias (positive results being more likely to be published than negative results) which is difficult to detect especially when based on a limited number of small studies. 15 REFERENCES 1. Senthamizhchelvan S. et al. Human biodistribution and radiation dosimetry of 82Rb. J Nucl Med, 2010; 51:1592 – 99. 2. Senthamizhchelvan S. et al. Radiation dosimetry of 82Rb in humans under pharmacologic stress. J Nucl Med 2011; 52: 485-91 3. Eckerman, K. F. et al. User’s Guide to the DCAL System, ORNL/TM-2001-190; Oak Ridge National Laboratory, Oak Ridge, TN, August, 2006. 4. Lederer, M and Shirley, V. Table of Isotopes, 7th Edition. 5. Judge, S et al. Applied radiation and isotopes (1987); vol 38, no. 3: pp 185-90. 6. Demer, L.L. et al. Assessment of coronary artery disease severity by PET: Comparison with quantitative arteriography in 193 patients. Circulation 1989; 79: 825-35. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CardioGen-82® (rubidium Rb 82 generator) consists of Sr-82 adsorbed on a hydrous stannic oxide column with an activity of 90-150 millicuries Sr-82 at calibration time. A lead shield surrounded by a labeled plastic container encases the generator. The container label provides complete assay data for each generator. Directions for determining the activity of Rb-82 eluted from the generator are described above [see Dosage and Administration (2.5)]. Use CardioGen-82 (rubidium Rb 82 Generator) only with an appropriate, properly calibrated infusion system labeled for use with the generator. Receipt, transfer, handling, possession or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate. 16.2 Disposal Licensee personnel should monitor the amount of radioactivity present within the generator prior to its disposal. Do not dispose of the generator in regular refuse systems. Store and/or dispose of the generator in accordance with the conditions of NRC radioactive materials license pursuant to 10 CFR, Part 20, or equivalent conditions pursuant to Agreement State Regulation. For questions about the disposal of the CardioGen-82 generator, contact Bracco Diagnostics Inc. at 1-800-447-6883, option 3. 16.3 Storage Store the generator at 20-25oC (68-77oF) [See USP]. 17 PATIENT COUNSELING INFORMATION 17.1 Women of Childbearing Potential Patients should be advised to inform their physician or healthcare provider if they are pregnant or breast- feeding. 17.2 Post-study Breastfeeding Avoidance Instruct nursing patients to substitute stored breast milk or infant formula for breast milk for one hour after administration of rubidium Rb 82 chloride injection. Reference ID: 3084430 11 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 17.3 Post-study Voiding Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after completion of the PET scan. Manufactured for Bracco Diagnostics Inc. Princeton, NJ 08543 by Medi-Physics, Inc., South Plainfield, NJ 07080 US Patent 7,504,646 Reference ID: 3084430 12 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Cardiogen-82 Assay Label CARDIOGEN-82 n (Rubidium Rb 82 Generator) Sr-82 Activity: Total Act. Sr-82 and Sr-85 Sr-85/Sr-82 Ratio: As of Noon EST Exp. Date: (see below) Lot No.: DECAY CHART Strontium Sr 82 Half Life 25 Days Fraction Fraction Fraction Days Remaining Days Remaining Days Remaining 0 1.000 16 0.642 32 0.412 2 0.946 18 0.607 34 0.390 4 0.895 20 0.574 36 0.369 6 0.847 22 0.543 38 0.349 8 0.801 24 0.514 40 0.330 10 0.758 26 0.486 42 0.312 12 0.717 28 0.460 14 0.678 30 0.435 *Calibration time Expiration Date: Stop use of the CardioGen-82 generator once any one of the following Expiration Limits is reached.  A total elution volume of 17 L has passed through the generator column, or  42 days post calibration date, or  An eluate Sr-82 level of 0.01 μCi /mCi Rb-82, or  An eluate Sr-85 level of 0.1 μCi /mCi Rb-82. Manufactured for: Bracco Diagnostics Inc., Princeton, NJ 08543 by Medi-Physics, Inc., South Plainfield, NJ 07080 46-8200xxxxx Reference ID: 3084430 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.464676	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019414s014lbl.pdf', 'application_number': 19414, 'submission_type': 'SUPPL ', 'submission_number': 14}
11,503	NDA 19-429/S-023 Page 3 Fiorinal with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate) capsule [Watson Pharmaceuticals, Inc.] Rx only DESCRIPTION Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is supplied in capsule form for oral administration. Each capsule contains the following active ingredients: butalbital, USP . . . . . . . . . . . . . . . . .50 mg aspirin, USP . . . . . . . . . . . . . . . . . .325 mg caffeine, USP . . . . . . . . . . . . . . . . . .40 mg codeine phosphate, USP . . . .. . . .30 mg Butalbital (5-allyl-5-isobutylbarbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural formula: Chemical Structure C11H16N2O3 molecular weight 224.26 Aspirin (benzoic acid, 2-(acetyloxy)-) is an analgesic, antipyretic, and anti-inflammatory. It has the following structural formula: Chemical Structure C9H8O4 molecular weight 180.16 Caffeine (1,3,7-trimethylxanthine) is a central nervous system stimulant. It has the following structural formula: Chemical Structure C8H10N4O2 molecular weight 194.19 Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is a narcotic analgesic and antitussive. It has the following structural formula: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 4 Chemical Structure C18H24NO7P anhydrous molecular weight 397.37 Inactive Ingredients: microcrystalline cellulose, pregelatinized starch, talc. Gelatin capsules contain D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, titanium dioxide. The capsules are printed with edible ink containing red iron oxide. CLINICAL PHARMACOLOGY Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is a combination drug product intended as a treatment for tension headache. Fiorinal® (Butalbital, Aspirin, and Caffeine Capsules, USP) consists of a fixed combination of caffeine 40 mg, butalbital 50 mg, and aspirin 325 mg. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood. Pharmacokinetics Bioavailability: The bioavailability of the components of the fixed combination of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is identical to their bioavailability when Fiorinal® (Butalbital, Aspirin, and Caffeine Capsules, USP) and codeine are administered separately in equivalent molar doses. The behavior of the individual components is described below. Aspirin The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption. During the absorption process and after absorption, aspirin is mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are loosely bound to plasma proteins. The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 5 The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate. The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose. See OVERDOSAGE for toxicity information. Codeine Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain, however, codeine is not bound to plasma proteins and does not accumulate in body tissues. The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. The bioavailability of the codeine component of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is equivalent to that of a solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 mg dose. See OVERDOSAGE for toxicity information. Butalbital Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility. Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 6 The bioavailability of the butalbital component of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose. The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. See OVERDOSAGE for toxicity information. Caffeine Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1 methylxanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug. The bioavailability of the caffeine component for Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1,660 ng/mL was obtained in less than an hour for an 80 mg dose. See OVERDOSAGE for toxicity information. INDICATIONS Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is indicated for the relief of the symptom complex of tension (or muscle contraction) headache. Evidence supporting the efficacy of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), codeine, Fiorinal® (Butalbital, Aspirin, and Caffeine Capsules, USP), and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours. Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) proved statistically significantly superior to each of its components (Fiorinal®, codeine) and to placebo on measures of pain relief. Evidence supporting the efficacy and safety of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable. CONTRAINDICATIONS Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is contraindicated under the following conditions: This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 7 1. Hypersensitivity or intolerance to aspirin, caffeine, butalbital or codeine. 2. Patients with a hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency and severe liver damage). 3. Patients with the syndrome of nasal polyps, angioedema and bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory drugs. Anaphylactoid reactions have occurred in such patients. 4. Peptic ulcer or other serious gastrointestinal lesions. 5. Patients with porphyria. WARNINGS Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking. Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders. Aspirin administered pre-operatively may prolong the bleeding time. In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries. Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions. Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is not recommended. Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu. PRECAUTIONS General Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, coagulation disorders, or head injuries, elevated This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 8 intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, prostatic hypertrophy, and peptic ulcer. Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects. Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma. Ultra-rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D62x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See PRECAUTIONS, Nursing Mothers) Information for Patients Patients should be informed that Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) contains aspirin and should not be taken by patients with an aspirin allergy. Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). Alcohol and other CNS depressants may produce an additive CNS depression when taken with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), and should be avoided. Codeine and butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. For information on use in geriatric patients, refer to PRECAUTIONS, Geriatric Use. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 9 Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services). Laboratory Tests In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests. Drug Interactions The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors. In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) may enhance the effects of: 1. Oral anticoagulants, causing bleeding by inhibiting prothrombin formation in the liver and displacing anticoagulants from plasma protein binding sites. 2. Oral antidiabetic agents and insulin, causing hypoglycemia by contributing an additive effect, if dosage of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) exceeds maximum recommended daily dosage. 3. 6-mercaptopurine and methotrexate, causing bone marrow toxicity and blood dyscrasias by displacing these drugs from secondary binding sites, and, in the case of methotrexate, also reducing its excretion. 4. Non-steroidal anti-inflammatory agents, increasing the risk of peptic ulceration and bleeding by contributing additive effects. 5. Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression. Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) may diminish the effects of: Uricosuric agents such as probenecid and sulfinpyrazone, reducing their effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites. Drug/Laboratory Test Interactions Aspirin: Aspirin may interfere with the following laboratory determinations in blood: serum amylase, fasting blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase (SGOT), uric acid, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 10 prothrombin time and bleeding time. Aspirin may interfere with the following laboratory determinations in urine: glucose, 5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric acid, diacetic acid, and spectrophotometric detection of barbiturates. Codeine: Codeine may increase serum amylase levels. Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies have been conducted in mice and rats with aspirin, alone or in combination with other drugs, in which no evidence of carcinogenesis was seen. No adequate studies have been conducted in animals to determine whether aspirin has a potential for mutagenesis or impairment of fertility. No adequate studies have been conducted in animals to determine whether butalbital has a potential for carcinogenesis, mutagenesis, or impairment of fertility. Usage in Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). It is also not known whether Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) should be given to a pregnant woman only when clearly needed. Nonteratogenic Effects Although Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) was not implicated in the birth defect, a female infant was born with lissencephaly, pachygyria and heterotopic gray matter. The infant was born 8 weeks prematurely to a woman who had taken an average of 90 Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) each month from the first few days of pregnancy. The child’s development was mildly delayed and from one year of age she had partial simple motor seizures. Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital containing drug during the last 2 months of pregnancy. Butalbital was found in the infant’s serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. Studies of aspirin use in pregnant women have not shown that aspirin increases the risk of abnormalities when administered during the first trimester of pregnancy. In controlled studies involving 41,337 pregnant women and their offspring, there was no evidence that aspirin taken during pregnancy caused stillbirth, neonatal death or reduced birth weight. In controlled studies of 50,282 pregnant women and their offspring, aspirin administration in moderate and heavy doses during the first four lunar months of pregnancy showed no teratogenic effect. Reproduction studies have been performed in rabbits and rats at doses up to 150 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to codeine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 11 Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy, regular use of aspirin in high doses may prolong pregnancy and delivery. Labor and Delivery Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate. Use of codeine during labor may lead to respiratory depression in the neonate. Nursing Mothers Aspirin, caffeine, barbiturates and codeine are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See PRECAUTIONS, General, Ultra-rapid Metabolizers of Codeine) Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 12 they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Commonly Observed The most commonly reported adverse events associated with the use of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) and not reported at an equivalent incidence by placebo-treated patients were nausea and/or abdominal pain, drowsiness, and dizziness. Associated with Treatment Discontinuation Of the 382 patients treated with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) in controlled clinical trials, three (0.8%) discontinued treatment with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) because of adverse events. One patient each discontinued treatment for the following reasons: gastrointestinal upset; lightheadedness and heavy eyelids; and drowsiness and generalized tingling. Incidence in Controlled Clinical Trials The following table summarizes the incidence rates of the adverse events reported by at least 1% of the Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) treated patients in controlled clinical trials comparing Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Adverse Events Reported by at Least 1% of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Body System/ Phosphate Capsules, USP) Placebo Adverse Event (N = 382) (N = 377) Central Nervous Drowsiness 2.4% 0.5% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 13 Adverse Events Reported by at Least 1% of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Body System/ Phosphate Capsules, USP) Placebo Adverse Event (N = 382) (N = 377) Dizziness/Lightheadedness 2.6% 0.5% Intoxicated Feeling 1.0% 0% Gastrointestinal Nausea/Abdominal Pain 3.7% 0.8% Other Adverse Events Reported During Controlled Clinical Trials The listing that follows represents the proportion of the 382 patients exposed to Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited. All reported adverse events, except those already presented in the previous table, are included. It is important to emphasize that, although the adverse events reported did occur while the patient was receiving Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), the adverse events were not necessarily caused by Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). Adverse events are classified by body system and frequency. “Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent. “Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients. All adverse events tabulated below are classified as infrequent. Central Nervous: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, and sluggishness. Autonomic Nervous: dry mouth and hyperhidrosis. Gastrointestinal: vomiting, difficulty swallowing, and heartburn. Cardiovascular: tachycardia. Musculoskeletal: leg pain and muscle fatigue. Genitourinary: diuresis. Miscellaneous: pruritus, fever, earache, nasal congestion, and tinnitus. Voluntary reports of adverse drug events, temporally associated with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), that have been received since market introduction and that were not reported in clinical trials by the patients treated with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP), are listed below. Many or most of these events may have no causal relationship with the drug and are listed according to body system. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 14 Central Nervous: Abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo. Autonomic Nervous: epistaxis, flushing, miosis, salivation. Gastrointestinal: anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasm, hiccup, mouth burning, pyloric ulcer. Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope. Skin: erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis. Urinary: kidney impairment, urinary difficulty. Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema. The following adverse drug events may be borne in mind as potential effects of the components of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). Potential effects of high dosage are listed in the OVERDOSAGE section of this insert. Aspirin: occult blood loss, hemolytic anemia, iron deficiency anemia, gastric distress, heartburn, nausea, peptic ulcer, prolonged bleeding time, acute airway obstruction, renal toxicity when taken in high doses for prolonged periods, impaired urate excretion, hepatitis. Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia. Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus. DRUG ABUSE AND DEPENDENCE Controlled Substance Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) is controlled by the Drug Enforcement Administration and is classified under Schedule III. Abuse and Dependence Codeine Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications. Butalbital Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 15 not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient’s regular dosage level and gradually decreasing the daily dosage as tolerated by the patient. OVERDOSAGE The toxic effects of acute overdosage of Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) are attributable mainly to the barbiturate and codeine components, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) overdosage is unlikely. Signs and Symptoms Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; hypovolemic shock. Symptoms attributable to acute aspirin poisoning include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting and abdominal pain; tinnitus, hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium; tachycardia and extrasystoles. Symptoms of acute codeine poisoning include the opioid triad of: pinpoint pupils, marked depression of respiration, and loss of consciousness. Convulsions may occur. Treatment The following paragraphs describe one approach to the treatment of overdose with Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP). However, because strategies for the management of an overdose continually evolve, consultation with a regional poison control center is strongly encouraged. Treatment consists primarily of management of barbiturate intoxication, reversal of the effects of codeine, and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate and 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood pressure is required, Norepinephrine Bitartrate (Levophed®) may be given I.V. with the usual precautions and serial blood pressure monitoring. In severe cases of intoxication, peritoneal This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 16 dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with vitamin K, intravenously. Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Typically, a dose of 0.4-2 mg is given parenterally and may be repeated if an adequate response is not achieved. Since the duration of action of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Up-to-date information about the treatment of overdose can be obtained from a Certified Regional Poison Control Center. Telephone numbers of Certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®. Toxic and Lethal Doses (for adults) Butalbital: toxic dose 1 g (20 capsules); lethal dose 2-5 g Aspirin: toxic blood level greater than 30 mg/100 mL; lethal dose 10-30 g Caffeine: toxic dose greater than 1 g; (25 capsules); lethal dose unknown Codeine: toxic dose 240 mg (8 capsules); lethal dose 0.5-1 g DOSAGE AND ADMINISTRATION One or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules. Extended and repeated use of this product is not recommended because of the potential for physical dependence. HOW SUPPLIED Fiorinal® with Codeine (Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) Blue cap with a yellow body. Cap is imprinted twice with “FIORINAL” and “CODEINE” in red. Body is imprinted twice with “WATSON 956” in red. Bottles of 100 are supplied with child-resistant closures. (NDC 52544-956-01) This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 17 Store and Dispense Below 25°C (77°F); tight container. Protect from moisture. Rx only Watson Pharmaceuticals, Inc. Corona, CA 92880 USA Revised: January 2007 FIORNCOD01/07 S0107 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 18 Butalbital, Aspirin, Caffeine and Codeine Phosphate (Butalbital, Aspirin, Caffeine and Codeine Phosphate) Capsule [Watson Laboratories, Inc.] Rx only DESCRIPTION Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is supplied in capsule form for oral administration. Each capsule contains the following active ingredients: butalbital, USP ……………………..50 mg aspirin, USP ……………………....325 mg caffeine, USP ………………………40 mg codeine phosphate, USP …………30 mg Butalbital (5-allyl-5-isobutylbarbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural formula: Chemical Structure C11H16N2O3 molecular weight 224.26 Aspirin (benzoic acid, 2-(acetyloxy)-) is an analgesic, antipyretic, and anti-inflammatory. It has the following structural formula: Chemical Structure C9H8O4 molecular weight 180.16 Caffeine (1,3,7-trimethylxanthine) is a central nervous system stimulant. It has the following structural formula: Chemical Structure C8H10N4O2 molecular weight 194.19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 19 Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is a narcotic analgesic and antitussive. It has the following structural formula: Chemical Structure C18H24NO7P anhydrous molecular weight 397.37 Inactive Ingredients: microcrystalline cellulose, pregelatinized starch, talc. Gelatin capsules contain D&C Yellow No.10, FD&C Blue No.1, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, titanium dioxide. The capsules are printed with edible ink containing red iron oxide. CLINICAL PHARMACOLOGY Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is a combination drug product intended as a treatment for tension headache. Butalbital, Aspirin, and Caffeine Capsules, USP consists of a fixed combination of caffeine 40 mg, butalbital 50 mg, and aspirin 325 mg. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood. Pharmacokinetics Bioavailability: The bioavailability of the components of the fixed combination of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is identical to their bioavailability when Butalbital, Aspirin, and Caffeine Capsules, USP and codeine are administered separately in equivalent molar doses. The behavior of the individual components is described below. Aspirin The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption. During the absorption process and after absorption, aspirin is mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are loosely bound to plasma proteins. The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3 hours. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 20 The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate. The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose. See OVERDOSAGE for toxicity information. Codeine Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain, however, codeine is not bound to plasma proteins and does not accumulate in body tissues. The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. The bioavailability of the codeine component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 mg dose. See OVERDOSAGE for toxicity information. Butalbital Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility. Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 21 The bioavailability of the butalbital component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose. The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. See OVERDOSAGE for toxicity information. Caffeine Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1 methylxanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug. The bioavailability of the caffeine component Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1,660 ng/mL was obtained in less than an hour for an 80 mg dose. See OVERDOSAGE for toxicity information. INDICATIONS Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is indicated for the relief of the symptom complex of tension (or muscle contraction) headache. Evidence supporting the efficacy of butalbital, aspirin, caffeine, and codeine phosphate capsules is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: butalbital, aspirin, caffeine, and codeine phosphate capsules; codeine; Butalbital, Aspirin, and Caffeine Capsules, USP; and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours. Butalbital, aspirin, caffeine, and codeine phosphate capsules proved statistically significantly superior to each of its components (Butalbital, Aspirin, and Caffeine Capsules, USP and codeine) and to placebo on measures of pain relief. Evidence supporting the efficacy and safety of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 22 CONTRAINDICATIONS Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated under the following conditions: 1. Hypersensitivity or intolerance to aspirin, caffeine, butalbital or codeine. 2. Patients with a hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency and severe liver damage). 3. Patients with the syndrome of nasal polyps, angioedema and bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory drugs. Anaphylactoid reactions have occurred in such patients. 4. Peptic ulcer or other serious gastrointestinal lesions. 5. Patients with porphyria. WARNINGS Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking. Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders. Aspirin administered pre-operatively may prolong the bleeding time. In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries. Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions. Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is not recommended. Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu. PRECAUTIONS General Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 23 renal or hepatic function, coagulation disorders, or head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, prostatic hypertrophy, and peptic ulcer. Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects. Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma. Ultra-rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D62x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See PRECAUTIONS, Nursing Mothers) Information for Patients Patients should be informed that Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains aspirin and should not be taken by patients with an aspirin allergy. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Alcohol and other CNS depressants may produce an additive CNS depression when taken with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, and should be avoided. Codeine and butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. For information on use in geriatric patients, refer to PRECAUTIONS, Geriatric Use. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 24 Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services). Laboratory Tests In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests. Drug Interactions The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors. In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may enhance the effects of: 1. Oral anticoagulants, causing bleeding by inhibiting prothrombin formation in the liver and displacing anticoagulants from plasma protein binding sites. 2. Oral antidiabetic agents and insulin, causing hypoglycemia by contributing an additive effect, if dosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP exceeds maximum recommended daily dosage. 3. 6-mercaptopurine and methotrexate, causing bone marrow toxicity and blood dyscrasias by displacing these drugs from secondary binding sites, and, in the case of methotrexate, also reducing its excretion. 4. Non-steroidal anti-inflammatory agents, increasing the risk of peptic ulceration and bleeding by contributing additive effects. 5. Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may diminish the effects of: Uricosuric agents such as probenecid and sulfinpyrazone, reducing their effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites. Drug/Laboratory Test Interactions Aspirin: Aspirin may interfere with the following laboratory determinations in blood: serum amylase, fasting blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase (SGOT), uric acid, prothrombin time and bleeding time. Aspirin may interfere with the following laboratory This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 25 determinations in urine: glucose, 5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric acid, diacetic acid, and spectrophotometric detection of barbiturates. Codeine: Codeine may increase serum amylase levels. Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies have been conducted in mice and rats with aspirin, alone or in combination with other drugs, in which no evidence of carcinogenesis was seen. No adequate studies have been conducted in animals to determine whether aspirin has a potential for mutagenesis or impairment of fertility. No adequate studies have been conducted in animals to determine whether butalbital has a potential for carcinogenesis, mutagenesis, or impairment of fertility. Usage in Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. It is also not known whether Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be given to a pregnant woman only when clearly needed. Nonteratogenic Effects Although Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP was not implicated in the birth defect, a female infant was born with lissencephaly, pachygyria and heterotopic gray matter. The infant was born 8 weeks prematurely to a woman who had taken an average of 90 butalbital, aspirin, caffeine, and codeine phosphate capsules each month from the first few days of pregnancy. The child’s development was mildly delayed and from one year of age she had partial simple motor seizures. Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital containing drug during the last 2 months of pregnancy. Butalbital was found in the infant’s serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. Studies of aspirin use in pregnant women have not shown that aspirin increases the risk of abnormalities when administered during the first trimester of pregnancy. In controlled studies involving 41,337 pregnant women and their offspring, there was no evidence that aspirin taken during pregnancy caused stillbirth, neonatal death or reduced birth weight. In controlled studies of 50,282 pregnant women and their offspring, aspirin administration in moderate and heavy doses during the first four lunar months of pregnancy showed no teratogenic effect. Reproduction studies have been performed in rabbits and rats at doses up to 150 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to codeine. Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy, regular use of aspirin in high doses may prolong pregnancy and delivery. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 26 Labor and Delivery Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate. Use of codeine during labor may lead to respiratory depression in the neonate. Nursing Mothers Aspirin, caffeine, barbiturates and codeine are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See PRECAUTIONS, General, Ultra-rapid Metabolizers of Codeine) Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of butalbital, aspirin, caffeine, and codeine phosphate capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 27 Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Commonly Observed The most commonly reported adverse events associated with the use of butalbital, aspirin, caffeine, and codeine phosphate capsules and not reported at an equivalent incidence by placebo-treated patients were nausea and/or abdominal pain, drowsiness, and dizziness. Associated with Treatment Discontinuation Of the 382 patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules in controlled clinical trials, three (0.8%) discontinued treatment with butalbital, aspirin, caffeine, and codeine phosphate capsules because of adverse events. One patient each discontinued treatment for the following reasons: gastrointestinal upset; lightheadedness and heavy eyelids; and drowsiness and generalized tingling. Incidence in Controlled Clinical Trials The following table summarizes the incidence rates of the adverse events reported by at least 1% of the butalbital, aspirin, caffeine, and codeine phosphate capsules treated patients in controlled clinical trials comparing butalbital, aspirin, caffeine, and codeine phosphate capsules to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Adverse Events Reported by at Least 1% of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Butalbital, Aspirin, Caffeine, and Body System/ Codeine Phosphate Capsules Placebo Adverse Event (N = 382) (N = 377) Central Nervous Drowsiness 2.4% 0.5% Dizziness/Lightheadedness 2.6% 0.5% Intoxicated Feeling 1.0% 0% Gastrointestinal Nausea/Abdominal Pain 3.7% 0.8% This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 28 Other Adverse Events Reported During Controlled Clinical Trials The listing that follows represents the proportion of the 382 patients exposed to butalbital, aspirin, caffeine, and codeine phosphate capsules while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited. All reported adverse events, except those already presented in the previous table, are included. It is important to emphasize that, although the adverse events reported did occur while the patient was receiving butalbital, aspirin, caffeine, and codeine phosphate capsules, the adverse events were not necessarily caused by butalbital, aspirin, caffeine, and codeine phosphate capsules. Adverse events are classified by body system and frequency. “Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent. “Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients. All adverse events tabulated below are classified as infrequent. Central Nervous: headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, and sluggishness. Autonomic Nervous: dry mouth and hyperhidrosis. Gastrointestinal: vomiting, difficulty swallowing, and heartburn. Cardiovascular: tachycardia. Musculoskeletal: leg pain and muscle fatigue. Genitourinary: diuresis. Miscellaneous: pruritus, fever, earache, nasal congestion, and tinnitus. Voluntary reports of adverse drug events, temporally associated with butalbital, aspirin, caffeine, and codeine phosphate capsules, that have been received since market introduction and that were not reported in clinical trials by the patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules, are listed below. Many or most of these events may have no causal relationship with the drug and are listed according to body system. Central Nervous: Abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo. Autonomic Nervous: epistaxis, flushing, miosis, salivation. Gastrointestinal: anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasm, hiccup, mouth burning, pyloric ulcer. Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope. Skin: erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis. Urinary: kidney impairment, urinary difficulty. Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 29 The following adverse drug events may be borne in mind as potential effects of the components of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Potential effects of high dosage are listed in the OVERDOSAGE section of this insert. Aspirin: occult blood loss, hemolytic anemia, iron deficiency anemia, gastric distress, heartburn, nausea, peptic ulcer, prolonged bleeding time, acute airway obstruction, renal toxicity when taken in high doses for prolonged periods, impaired urate excretion, hepatitis. Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia. Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus. DRUG ABUSE AND DEPENDENCE Controlled Substance Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is controlled by the Drug Enforcement Administration and is classified under Schedule III. Abuse and Dependence Codeine Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications. Butalbital Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient’s regular dosage level and gradually decreasing the daily dosage as tolerated by the patient. OVERDOSAGE The toxic effects of acute overdosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are attributable mainly to the barbiturate and codeine components, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP overdosage is unlikely. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 30 Signs and Symptoms Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; hypovolemic shock. Symptoms attributable to acute aspirin poisoning include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting and abdominal pain; tinnitus, hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium; tachycardia and extrasystoles. Symptoms of acute codeine poisoning include the opioid triad of: pinpoint pupils, marked depression of respiration, and loss of consciousness. Convulsions may occur. Treatment The following paragraphs describe one approach to the treatment of overdose with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. However, because strategies for the management of an overdose continually evolve, consultation with a regional poison control center is strongly encouraged. Treatment consists primarily of management of barbiturate intoxication, reversal of the effects of codeine, and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate and 5% dextrose in water. Meticulous attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood pressure is required, Norepinephrine Bitartrate (Levophed®) may be given I.V. with the usual precautions and serial blood pressure monitoring. In severe cases of intoxication, peritoneal dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with vitamin K, intravenously. Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Typically, a dose of 0.4-2 mg is given parenterally and may be repeated if an adequate response is not achieved. Since the duration of action of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Up-to-date information about the treatment of overdose can be obtained from a Certified Regional Poison Control Center. Telephone numbers of Certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-429/S-023 Page 31 Toxic and Lethal Doses (for adults) Butalbital: toxic dose 1 g (20 capsules); lethal dose 2-5 g Aspirin: toxic blood level greater than 30 mg/100 mL; lethal dose 10-30 g Caffeine: toxic dose greater than 1 g; (25 capsules); lethal dose unknown Codeine: toxic dose 240 mg (8 capsules); lethal dose 0.5-1 g DOSAGE AND ADMINISTRATION One or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules. Extended and repeated use of this product is not recommended because of the potential for physical dependence. HOW SUPPLIED Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP Blue cap with a yellow body. Cap is imprinted with “WATSON” in red. Body is imprinted with “3546” in red. Supplied in bottles of 100 and 500. Bottles of 100 are supplied with child-resistant closures. Store and Dispense Below 25°C (77°F); tight container. Protect from moisture. Rx only Watson Laboratories, Inc. Corona, CA 92880 USA Revised: January 2007 BASPCC01/07 S0107 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.636357	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019429s023lbl.pdf', 'application_number': 19429, 'submission_type': 'SUPPL ', 'submission_number': 23}
11,505	---------- EPIPEN®- epinephrine injection EPIPEN Jr®- epinephrine injection Mylan Specialty L.P. EpiPen® (epinephrine) Auto-Injector 0.3 mg EpiPen® = one dose of 0.30 mg epinephrine (USP, 1:1000, 0.3 mL) EpiPen Jr® (epinephrine) Auto-Injector 0.15 mg EpiPenJr® = one dose of 0.15 mg epinephrine (USP, 1:2000, 0.3 mL) DESCRIPTION Each EpiPen® Auto-Injector delivers a single dose of 0.3 mg epinephrine injection, USP, 1:1000 (0.3 mL) in a sterile solution. Each EpiPen Jr® Auto-Injector delivers a single dose of 0.15 mg epinephrine injection, USP, 1:2000 (0.3 mL) in a sterile solution. The EpiPen and EpiPen Jr Auto-Injectors each contain 2 mL epinephrine solution. Approximately 1.7 mL remains in the auto- injector after activation and cannot be used. Each 0.3 mL in the EpiPen Auto-Injector contains 0.3 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0. Each 0.3 mL in the EpiPen Jr Auto-Injector contains 0.15 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0. Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is B-(3, 4-dihydroxyphenyl)-a-methyl-aminoethanol, with the following structure: structural formula Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the Reference ID: 3176782 formation of melanin. Replace EpiPen and EpiPen Jr Auto-Injectors if the epinephrine solution appears discolored. EpiPen and EpiPen Jr Auto-Injectors do not contain latex. CLINICAL PHARMACOLOGY Epinephrine is the drug of choice for the emergency treatment of severe allergic reactions (Type I) to insect stings or bites, foods, drugs, and other allergens. It can also be used in the treatment of anaphylaxis of unknown cause (idiopathic anaphylaxis) or exercise- induced anaphylaxis. When given intramuscularly or subcutaneously it has a rapid onset and short duration of action. Epinephrine acts on both alpha and beta adrenergic receptors. Through its action on alpha adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder. INDICATIONS AND USAGE EpiPen and EpiPen Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (see DOSAGE AND ADMINISTRATION section). Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, Reference ID: 3176782 dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate self- administration as emergency supportive therapy only and are not a substitute for immediate medical care. CONTRAINDICATIONS There are no absolute contraindications to the use of epinephrine in a life-threatening situation. WARNINGS EpiPen and EpiPen Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis (see ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary Reference ID: 3176782 artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature). Do not refrigerate. Before using, check to make sure the solution in the auto- injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate. PRECAUTIONS (1) General EpiPen and EpiPen Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision. Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used. It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION). Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other antiarrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid Reference ID: 3176782 individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen Jr Auto- Injector. Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen or EpiPen Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. (2) Information for Patients Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen/EpiPen Jr Auto-Injector carton. Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson's disease may notice a temporary worsening of symptoms. In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas (see ADVERSE REACTIONS). The carrier tube is not waterproof. The blue safety release helps prevent accidental injection and should be kept on until it will be used. (3) Drug Interactions Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias. Reference ID: 3176782 The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripe-lennamine and diphenhydramine. The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine. (4) Carcinogenesis, Mutagenesis, Impairment of Fertility Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay. Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE. (5) Usage in Pregnancy Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if epinephrine passes into your breast milk. Reference ID: 3176782 ADVERSE REACTIONS Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs (see PRECAUTIONS, Drug Interactions). Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life- threatening allergic reaction. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. OVERDOSAGE Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug. Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the Reference ID: 3176782 ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propranolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Suitable corrective measures must be taken in such situations. DOSAGE AND ADMINISTRATION EpiPen or EpiPen Jr Auto-Injector prescribers should ensure that the patient or caregiver understands the indications and use of this product. A health care provider should review the patient instructions and operation of the EpiPen or EpiPen Jr Auto-Injector, in detail, with the patient or caregiver. Inject EpiPen or EpiPen Jr intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. See detailed Directions for Use on the accompanying Patient Instructions. Selection of the appropriate dosage strength is determined according to patient body weight. EpiPen Auto-Injector delivers 0.3 mg epinephrine injection (0.3 mL, 1:1000) and is intended for patients who weigh 30 kg or more (approximately 66 pounds or more). EpiPen Jr Auto-Injector delivers 0.15 mg epinephrine injection (0.3 mL, 1:2000) and is intended for patients who weigh 15 to 30 kg (33 - 66 pounds). Each EpiPen or EpiPen Jr Auto-Injector contains a single dose of epinephrine. Since the doses of epinephrine delivered from EpiPen or EpiPen Jr Auto-Injector are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. The prescriber should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is indicated. With severe persistent anaphylaxis, repeat injections with an additional EpiPen Auto-Injector may be necessary. Patients should be instructed to periodically visually inspect the epinephrine solution for particulate matter and discoloration. If the solution contains particulate matter or develops a pinkish or brown color, the patient should immediately contact their physician for a replacement, since these changes indicate that the effectiveness of the drug product may be decreased. Reference ID: 3176782 HOW SUPPLIED EpiPen Auto-Injectors (epinephrine injections, USP, 1:1000, 0.3 mL) are available in individual cartons, NDC 49502-500-01, and as EpiPen 2-Pak®, NDC 49502-500-02, a pack that contains two EpiPen Auto- Injectors (epinephrine injections, USP, 1:1000, 0.3 mL) and one EpiPen Auto-Injector trainer device. EpiPen Jr Auto-Injectors (epinephrine injection, USP, 1:2000, 0.3 mL) are available in individual cartons, NDC 49502-501-01, and as EpiPen Jr 2-Pak®, NDC 49502-501-02, a pack that contains two EpiPen Jr Auto-Injectors (epinephrine injections, USP, 1:2000, 0.3 mL) and one EpiPen Auto-Injector trainer device. EpiPen 2-Pak® and EpiPen Jr 2-Pak® also includes an S-clip to clip two cases together. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C 30°C (59°F-86°F) (See USP Controlled Room Temperature). Contains no latex. Protect from light. Rx only. MANUFACTURED FOR Mylan Specialty L.P., Napa, CA 94558, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company EpiPen®, EpiPen Jr®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly- owned affiliate, Mylan Specialty L.P. of Napa, CA 94558, USA 08/12 0001600 03-914-01 Reference ID: 3176782 PATIENT INFORMATION Epipen For allergic emergencies (anaphylaxis) Read this Patient Information Leaflet carefully before using the EpiPen® Auto-Injector or EpiPen Jr® Auto-Injector and each time you get a refill. There may be new information. You should know how to use the EpiPen or EpiPen Jr Auto-Injector before you have an allergic emergency. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about the EpiPen and EpiPen Jr Auto-Injector? 1. EpiPen and EpiPen Jr Auto-Injectors contain epinephrine, a medicine used to treat allergic emergencies (anaphylaxis). Anaphylaxis can be life threatening, can happen within minutes, and can be caused by stinging and biting insects, allergy injections, foods, medicines, exercise, or unknown causes. Symptoms of anaphylaxis may include:  trouble breathing  wheezing  hoarseness (changes in the way your voice sounds)  hives (raised reddened rash that may itch)  severe itching  swelling of your face, lips, mouth, or tongue  skin rash, redness, or swelling  fast heartbeat  weak pulse  feeling very anxious  confusion  stomach pain  losing control of urine or bowel movements (incontinence)  dizziness, fainting, or “passing out” (unconsciousness) 2. Always carry your EpiPen or EpiPen Jr Auto-Injector with you because you may not know when anaphylaxis may happen. Talk to your healthcare provider if you need additional units to keep at work, school, or other locations. Tell your family members and Reference ID: 3176782 others where you keep your EpiPen or EpiPen Jr Auto-Injector and how to use it before you need it. You may be unable to speak in an allergic emergency. 3. When you have an allergic emergency (anaphylaxis) use the EpiPen or EpiPen Jr Auto-Injector right away. Get emergency medical help right away. You may need further medical attention. You may need a second EpiPen or EpiPen Jr Auto-Injector should symptoms persist or recur. More than two sequential doses of epinephrine for a single episode should only be administered by a healthcare provider. What are the EpiPen and EpiPen Jr Auto-Injectors?  EpiPen and EpiPen Jr Auto-Injector are disposable, prefilled automatic injection devices used to treat life-threatening, allergic emergencies including anaphylaxis in people who are at risk for or have a history of serious allergic emergencies. They contain a single dose of epinephrine.  EpiPen and EpiPen Jr Auto-Injector are for immediate self (or caregiver) administration and do not take the place of emergency medical care. You should get emergency help right away after using the EpiPen and EpiPen Jr Auto Injector.  EpiPen and EpiPen Jr Auto-Injector are for people who have been prescribed this medication by their healthcare provider. • The EpiPen Auto-Injector (0.3 mg) is for patients who weigh 66 pounds or more (30 kilograms or more). • The EpiPen Jr Auto-Injector (0.15 mg) is for patients who weigh about 33 to 66 pounds (15 to 30 kilograms). • It is not known if EpiPen and EpiPen Jr Auto-Injectors are safe and effective in children who weigh less than 33 pounds (15 kilograms). What should I tell my healthcare provider before using the EpiPen or EpiPen Jr Auto- Injector? Before you use EpiPen or EpiPen Jr Auto-Injector, tell your healthcare provider about all your medical conditions, but especially if you:  have heart problems or high blood pressure  have diabetes  have thyroid conditions  have asthma  have a history of depression  have Parkinson’s disease  have any other medical conditions  are pregnant or plan to become pregnant. It is not known if epinephrine will harm your unborn baby.  are breastfeeding or plan to breastfeed. It is not known if epinephrine passes into your breast milk. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Inform your healthcare provider Reference ID: 3176782 of all known allergies. Especially tell your healthcare provider if you take certain asthma medications. EpiPen or EpiPen Jr Auto-Injector and other medicines may affect each other, causing side effects. EpiPen or EpiPen Jr Auto-Injector may affect the way other medicines work, and other medicines may affect how the EpiPen or EpiPen Jr Auto-Injector works. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Use your EpiPen or EpiPen Jr Auto-Injector for treatment of anaphylaxis as prescribed by your healthcare provider, regardless of medical conditions or medication. How should I use the EpiPen and EpiPen Jr Auto-Injector?  Each EpiPen or EpiPen Jr Auto-Injector contains only 1 dose of medicine.  The EpiPen or EpiPen Jr Auto-Injector should be injected into the muscle of your outer thigh. It can be injected through your clothing if needed.  Read the Instructions for Use at the end of this Patient Information Leaflet about the right way to use EpiPen and EpiPen Jr Auto-Injector.  Use your EpiPen or EpiPen Jr Auto-Injector exactly as your healthcare provider tells you to use it.  Caution: Never put your thumb, fingers, or hand over the orange tip. Never press or push the orange tip with your thumb, fingers, or hand. The needle comes out of the orange tip. Accidental injection into finger, hands or feet may cause a loss of blood flow to these areas. If this occurs, go immediately to the nearest emergency room. Tell the healthcare provider where on your body you received the accidental injection.  Your EpiPen and EpiPen Jr Auto-Injector may come packaged with an EpiPen Auto- Injector Trainer and separate Trainer Instructions for Use. The EpiPen Auto-Injector Trainer has a grey color. The grey EpiPen Auto-Injector Trainer contains no medicine and no needle. Practice with your EpiPen Auto-Injector Trainer before an allergic emergency happens to make sure you are able to safely use the real EpiPen and EpiPen Jr Auto-Injector in an emergency. Always carry your real EpiPen or EpiPen Jr Auto-Injector with you in case of an allergic emergency. Additional training resources are available at www.epipen.com.  Do not drop the carrier tube or auto-injector. If the carrier tube or auto-injector is dropped, check for damage and leakage. Discard the auto-injector and carrier tube, and replace if damage or leakage is noticed or suspected. What are the possible side effects of the EpiPen and EpiPen Jr Auto-Injector? EpiPen and EpiPen Jr Auto-Injector may cause serious side effects.  The EpiPen or EpiPen Jr Auto-Injector should only be injected into the middle of your outer thigh (upper leg). Do not inject the EpiPen or EpiPen Jr Auto-Injector into Reference ID: 3176782 your:  vein  buttock  fingers, toes, hands, or feet If you accidentally inject EpiPen or EpiPen Jr Auto-Injector into any other part of your body, go immediately to the nearest emergency room. Tell the healthcare provider where on your body you received the accidental injection. If you have certain medical conditions, or take certain medicines, your condition may get worse or you may have longer lasting side effects when you take the EpiPen or EpiPen Jr Auto-Injector. Talk to your healthcare provider about all your medical conditions. Common side effects of the EpiPen and EpiPen Jr Auto-Injector include:  fast, irregular or “pounding” heartbeat  sweating  headache  weakness or shakiness  paleness  feelings of over excitement, nervousness or anxiety  dizziness  nausea and/or vomiting  breathing problems These side effects may go away with rest. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of the EpiPen or EpiPen Jr Auto-Injector. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store the EpiPen and EpiPen Jr Auto-Injector?  Store at 68° to 77° F (20° to 25° C)  Protect from light.  Do not expose to extreme cold or heat. For example, do not store in your vehicle’s glove box and do not store in the refrigerator or freezer.  Examine contents in the clear window of your auto-injector periodically. The solution should be clear. If the solution is discolored (pinkish or brown color) or contains solid particles, replace the unit.  Always keep your EpiPen or EpiPen Jr Auto-Injector in the carrier tube to protect it from damage; however, the carrier tube is not waterproof.  The blue safety release helps to prevent accidental injection of the device. Keep the Reference ID: 3176782 blue safety release on until you need to use it.  Your EpiPen or EpiPen Jr Auto-Injector has an expiration date. Replace it before the expiration date. General information about the safe and effective use of the EpiPen and EpiPen Jr Auto- Injector: Do not use the EpiPen or EpiPen Jr Auto-Injector for a condition for which it was not prescribed. Do not give your EpiPen or EpiPen Jr Auto-Injector to other people. This Patient Information Leaflet summarizes the most important information about the EpiPen and EpiPen Jr Auto-Injectors. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about the EpiPen and EpiPen Jr Auto-Injector that is written for health professionals. For more information and video instructions on the use of the EpiPen and EpiPen Jr Auto- Injector, go to www.epipen.com or call 1-800-395-3376. What are the ingredients in EpiPen and EpiPen Jr Auto-Injector? Active Ingredients: Epinephrine Inactive Ingredients: sodium chloride, sodium metabisulfite, hydrochloric acid, and water. The EpiPen and EpiPen Jr Auto-Injector contain no latex. Important Information • The EpiPen Auto-Injector has a yellow colored label. • The EpiPen Jr Auto-Injector has a green colored label. • The EpiPen Trainer has a grey color, and contains no medicine and no needle. • Your auto-injector is designed to work through clothing. • The blue safety release on the EpiPen and EpiPen Jr Auto-Injector helps to prevent accidental injection of the device. Keep the blue safety release on until you need to use it. • Only inject into outer thigh. Never inject into any other part of the body. • Never put your thumb, fingers, or your hand over the orange tip. The needle comes out of the orange tip. • If an accidental injection happens, get medical help right away. • Do not place patient information or any other foreign objects in carrier with Auto-Injector, as this may prevent you from removing the Auto-Injector for use Instructions for Use Carefully read these Instructions for Use before you need to use your EpiPen or EpiPen Jr Auto- Injector. Before you use your EpiPen or EpiPen Jr Auto-Injector, make sure your healthcare provider shows you the right way to use it. If you have any questions, ask your healthcare pro vider. Reference ID: 3176782 Your EpiPen and EpiPen Jr Auto-Injector EpiPen and EpiPen Je Injector 3‐Step Easy To Follow Instructions: 1. Prepare the EpiPen or EpiPen Jr Auto-Injector For Injection 2. Administer the EpiPen or EpiPen Jr Auto-Injector 3. Finalize the Injection Process (See detailed instructions below) 1. Prepare the EpiPen or EpiPen Jr Auto-Injector For Injection Remove the auto-injector from the clear carrier tube. instructional use Flip open the yellow cap of your EpiPen or the green cap of your EpiPen Jr Auto-Injector carrier tube. instructional use Tip and slide the auto-injector out of the carrier tube. Reference ID: 3176782 instructional use Grasp the auto-injector in your fist with the orange tip pointing downward. With your other hand, remove the blue safety release by pulling straight up without bending or twisting it. Note:  The needle comes out of the orange tip.  Never put your thumb, fingers or hand over the orange tip. 2. Administer the EpiPen or EpiPen Jr Auto-Injector instructional use Hold the auto-injector with orange tip near the outer thigh. Swing and firmly push the orange tip against the outer thigh until it ‘clicks’. Keep the auto-injector firmly pushed against the thigh at a 90° angle (perpendicular) to the thigh. instructional use Hold firmly against the thigh for approximately 10 seconds to deliver the drug. The injection is now complete. 3. Finalize the Injection Process Reference ID: 3176782 Remove the auto-injector from the thigh. The orange tip will extend to cover the needle. instructional useinstructional use Massage the injection area for 10 seconds. Get emergency medical help right away. You may need further medical attention. You may need a second EpiPen or EpiPen Jr Auto-Injector should symptoms persist or recur. Note:  Take your used auto-injector with you when you go to see the healthcare provider.  Tell the healthcare provider that you have received an injection of epinephrine. Show the healthcare provider where you received the injection.  Give your used EpiPen or EpiPen Jr Auto-Injector to a healthcare provider for inspection and proper disposal.  Ask for a refill, if needed. • The used auto-injector with extended needle cover will not fit in the carrier tube. • Most of the liquid medicine stays in the auto-injector and cannot be reused. You have received the correct dose of the medicine if the orange needle tip is extended and the window is blocked. • Your EpiPen and EpiPen Jr Auto-Injector may come packaged with an EpiPen Auto- Injector Trainer and separate Trainer Instructions for Use. The EpiPen Trainer has a grey color. The grey EpiPen Trainer contains no medicine and no needle. Practice with your EpiPen Trainer, but always carry your real EpiPen or EpiPen Jr Auto-Injector in case of an allergic emergency. • Do not attempt to take the EpiPen or EpiPen Jr Auto-Injector apart. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Specialty L.P., Napa, CA 94558, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company Reference ID: 3176782 EpiPen® and EpiPen Jr® are registered trademarks of Mylan Inc. licensed exclusively to its wholly- owned affiliate, Mylan Specialty L.P. of Napa, CA 94558, USA ©2012 by Meridian Medical Technologies®, Inc. 8/2012 03-855-03 0001726 Epipen Register your EpiPen or EpiPen Jr Auto-Injector at MyEpiPen.com and find out more about: • Free EpiPen Auto-Injector Refill Reminder Program. It is important to keep your auto-injector up-to date. Register up to 6 EpiPen or EpiPen Jr Auto-Injectors and receive automatic Refill Reminder Alerts. • Receive periodic information related to allergies and allergens. • Instructional Video For more information about EpiPen or EpiPen Jr Auto-Injectors and proper use of the product, visit www.epipen.com. Reference ID: 3176782 EpiPen® TRAINER INSTRUCTIONS FOR USE PRACTICE INSTRUCTIONS 1679 EpiPen® Trainer Instructions For Use 0001679 EpiPen Trainer Instructions for Use In an emergency: Do not use the grey Trainer. Use your yellow EpiPen® or green EpiPen Jr® Auto-Injector. Important Information  The Trainer label has a grey color.  The Trainer contains no medicine and no needle.  Practice with the grey colored Trainer before an allergic emergency (anaphylaxis) happens to make sure you are able to safely use the real yellow EpiPen or green EpiPen Jr Auto-Injector in case of an emergency.  Always carry your real EpiPen or EpiPen Jr Auto-Injector in case of an allergic emergency. Practice Instructions Familiarize yourself with this grey Trainer. Practice until you are comfortable using it. Your grey colored Trainer: Epipen  Never put your thumb, other fingers, or hand over the Orange Tip.  The Orange Tip is where the needle comes out of your EpiPen or EpiPen Jr Auto-Injector. Reference ID: 3176782 EASY TO FOLLOW 1-2-3 DIRECTIONS 3-Step Easy to Follow Instructions instructional use 1 Prepare the Trainer For Simulated Injection  Grasp the grey Trainer in your fist with the orange tip pointing downward  With your other hand, remove blue safety release by pulling straight up without bending or twisting it  Removing the blue safety release unlocks the Trainer instructional useinstructional use 3 To reset the Trainer  Put the blue safety release back on the Trainer  Place the orange tip on a hard surface.  Squeeze the sides of the orange tip and push down on the Trainer with the other hand Note: With the actual yellow EpiPen or green EpiPen Jr Auto-Injector, the orange tip covers the needle after self-injection to help protect you from accidentally sticking yourself or others. Reference ID: 3176782 EACH PRACTICE SESSION Practice Session Information CAUTION: Caution: In case of an allergic emergency, use the real yellow EpiPen or green EpiPen Jr Auto- Injector and not the grey Trainer. Follow instructions above. Repeat as often as needed until you are able to self-inject quickly and correctly. Reread: • These Trainer Instructions for Use • The “Patient Information” that comes with your EpiPen or EpiPen Jr Auto-Injector Train others who could help you in an emergency: • Your parents, teachers, or friends should know how to help you during an allergic emergency (anaphylaxis). Before an emergency occurs, have them: • Practice activating the Trainer • Read these Trainer Instructions and the “Patient Information” For more information about the EpiPen and EpiPen Jr Auto-Injector and the proper use of the products, go to www.epipen.com. Important differences between the Trainer and your yellow EpiPen or green EpiPen Jr Auto-Injector EpiPen Contains medication? --No --------------------------------------------- Yes Has needle? -------------No --------------------------------------------- Yes Comes in Carrier Tube?-No --------------------------------------------- Yes Color of label ----------- Grey ---------------------------------------Yellow (EpiPen) Green (EpiPen Jr) Has expiration date? --- No --------------------------------------------- Yes Can be reused? ---------Yes -----------------------------------------No (use only once) Okay to remove and Replace safety release? -Yes ----------------------------------No (remove just once before use) Pressure needed to hold against thigh -------------Moderate ------------------------------------ Strong This Trainer Instructions for Use has been approved by the U.S. Food and Drug Administration. Reference ID: 3176782 Manufactured for Mylan Specialty L.P., Napa, CA 94558, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company EpiPen® and EpiPen Jr® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L.P. of Napa, CA 94558, USA ©2012 by Meridian Medical Technologies®, Inc. 03-856-01 8/12 0001679 Reference ID: 3176782	custom-source	2025-02-12T13:45:24.729931	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019430s053lbl.pdf', 'application_number': 19430, 'submission_type': 'SUPPL ', 'submission_number': 53}
11,504	PRESCRIBING INFORMATION logo fo ep ipen and epipen jr, respectively DESCRIPTION Each EpiPen® Auto-Injector delivers a single dose of 0.3 mg epinephrine injection, USP, 1:1000 (0.3 mL) in a sterile solution. Each EpiPen® Jr Auto-Injector delivers a single dose of 0.15 mg epinephrine injection, USP, 1:2000 (0.3 mL) in a sterile solution. The EpiPen® and EpiPen® Jr Auto-Injectors each contain 2 mL epinephrine solution. Approximately 1.7 mL remains in the auto-injector after activation and cannot be used. Each 0.3 mL in the EpiPen® Auto-Injector contains 0.3 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0. Each 0.3 mL in the EpiPen® Jr Auto-Injector contains 0.15 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0. Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is B-(3, 4 dihydroxyphenyl)-a-methyl-aminoethanol, with the following structure: Chemical Structure Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. Replace EpiPen® and EpiPen® Jr Auto-Injectors if the epinephrine solution appears discolored. EpiPen® and EpiPen® Jr Auto-Injectors do not contain latex. CLINICAL PHARMACOLOGY Epinephrine is the drug of choice for the emergency treatment of severe allergic reactions (Type I) to insect stings or bites, foods, drugs, and other allergens. It can also be used in the treatment of anaphylaxis of unknown cause (idiopathic anaphylaxis) or exercise-induced anaphylaxis. When given intramuscularly or subcutaneously it has a rapid onset and short duration of action. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2 Epinephrine acts on both alpha and beta adrenergic receptors. Through its action on alpha adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder. INDICATIONS AND USAGE EpiPen® and EpiPen® Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen® and EpiPen® Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (See DOSAGE AND ADMINISTRATION section). Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. EpiPen® and EpiPen® Jr Auto-Injectors are intended for immediate self-administration as emergency supportive therapy only and are not a substitute for immediate medical care. CONTRAINDICATIONS There are no absolute contraindications to the use of epinephrine in a life-threatening situation. WARNINGS EpiPen® and EpiPen® Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis. (See ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life- threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature). Do not refrigerate. Before using, check to make sure the solution in the auto- injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate. PRECAUTIONS (1) General EpiPen® and EpiPen® Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision. Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used. It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION). Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen® Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen® Jr Auto-Injector. Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen® or EpiPen® Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. (2) Information for Patients Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen®/EpiPen® Jr Auto-Injector carton. Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms. In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen® Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas. (See ADVERSE REACTIONS). (3) Drug Interactions Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine. The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 5 (4) Carcinogenesis, Mutagenesis, Impairment of Fertility Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay. Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE. (5) Usage in Pregnancy Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. ADVERSE REACTIONS Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs [see PRECAUTIONS, Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. OVERDOSAGE Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 6 Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propanolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure. Suitable corrective measures must be taken in such situations. DOSAGE AND ADMINISTRATION EpiPen® or EpiPen® Jr Auto-Injector prescribers should ensure that the patient or caregiver understands the indications and use of this product. A health care provider should review the patient instructions and operation of the EpiPen® or EpiPen® Jr Auto-Injector, in detail, with the patient or caregiver. Inject EpiPen® or EpiPen® Jr intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. See detailed Directions for Use on the accompanying Patient Instructions. Selection of the appropriate dosage strength is determined according to patient body weight. EpiPen® Auto-Injector delivers 0.3 mg epinephrine injection (0.3 mL, 1:1000) and is intended for patients who weigh 30 kg or more (approximately 66 pounds or more). EpiPen® Jr Auto-Injector delivers 0.15 mg epinephrine injection (0.3 mL, 1:2000) and is intended for patients who weigh 15 to 30 kg (33 – 66 pounds). Each EpiPen® or EpiPen® Jr Auto-Injector contains a single dose of epinephrine. Since the doses of epinephrine delivered from EpiPen® and EpiPen® Jr Auto-Injector are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. The prescriber should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is indicated. With severe persistent anaphylaxis, repeat injections with an additional EpiPen® Auto-Injector may be necessary. Patients should be instructed to periodically visually inspect the epinephrine solution for particulate matter and discoloration. If the solution contains particulate matter or develops a pinkish color or becomes darker than slightly yellow, the patient should immediately contact This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 7 their physician for a replacement, since these changes indicate that the effectiveness of the drug product may be decreased. HOW SUPPLIED EpiPen® Auto-Injectors (epinephrine injections, USP, 1:1000, 0.3 mL) are available in individual cartons, NDC 49502-500-01, and as EpiPen 2-Pak®, NDC 49502-500-02, a pack that contains two EpiPen® Auto-Injectors (epinephrine injections, USP, 1:1000, 0.3 mL) and one EpiPen® Auto-Injector trainer device. EpiPen® Jr Auto-Injectors (epinephrine injection, USP, 1:2000, 0.3 mL) are available in individual cartons, NDC 49502-501-01, and as EpiPen Jr 2-Pak®, NDC 49502-501-02, a pack that contains two EpiPen® Jr Auto-Injectors (epinephrine injections, USP, 1:2000, 0.3 mL) and one EpiPen® Auto-Injector trainer device. EpiPen 2-Pak® and EpiPen Jr 2-Pak® also includes a S-clip to clip two cases together. Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) (See USP Controlled Room Temperature). Contains no latex. Protect from light. Rx only. MANUFACTURED FOR Dey, L.P., NAPA, CALIFORNIA 94558, U.S.A. by Meridian Medical Technologies, Inc., a subsidiary of King Pharmaceuticals®, Inc., Columbia, MD 21046, U.S.A. EpiPen®, EpiPen® Jr, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan, Inc. licensed exclusively to its wholly-owned affiliate, Dey, L.P. of Napa California, USA. 09/08 0001222 03-500-03 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.822552	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019430s044lbl.pdf', 'application_number': 19430, 'submission_type': 'SUPPL ', 'submission_number': 44}
11,506	NDA 19-452/S-016/S-019 & S-020 Page 4 Derma-Smoothe/FS® fluocinolone acetonide Topical Oil, 0.01% (Body Oil) For Topical Use Only- NDC 28105-150-04 Not for Not for Oral, Ophthalmic, or Intravaginal Use DESCRIPTION Derma-Smoothe/FS® Topical Oil contains fluocinolone acetonide {(6α, 11β, 16α)-6,9-difluoro-11,21- dihydroxy-16,17[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione, cyclic 16,17 acetal with acetone}, a synthetic corticosteroid for topical dermatologic use. This formulation is also marketed as Derma-Smoothe/FS®,0.01% fluocinolone acetonide for use as scalp oil with “shower caps” for scalp psoriasis in adults and as fluocinone acetonide oil, 0.01% for chronic eczematous external otitis. Chemically, fluocinolone acetonide is C24 H30 F2 O6. It has the following structural formula: Fluocinolone acetonide in Derma-Smoothe/FS® has a molecular weight of 452.50. It is a white crystalline powder that is odorless, stable in light, and melts at 270°C with decomposition; soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water. Each gram of Derma-Smoothe/FS® contains approximately 0.11 mg of fluocinolone acetonide in a blend of oils, which contains isopropyl alcohol, isopropyl myristate, light mineral oil, oleth-2, refined peanut oil NF and fragrances. CLINICAL PHARMACOLOGY Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusion of topical corticosteroids can enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Also, inflammation and/or other disease processes in the skin can increase percutaneous absorption. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 5 Derma-Smoothe/FS® is in the low to medium range of potency as compared with other topical corticosteroids. CLINICAL STUDIES In a vehicle-controlled study for the treatment of psoriasis of the scalp in adults, after 21 days of treatment, 60% of patients on active treatment and 21% of patients on the drug vehicle had excellent to cleared clinical response. Open-label safety studies on 33 children (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis, and baseline body surface area involvement greater than 75% in 18 patients, and 50% to 75% in 15 patients, were treated with Derma-Smoothe/FS® twice daily for 4 weeks. Morning pre-stimulation cortisol level and post-Cortrosyn stimulation cortisol level were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal: cortisol > 7µg/dL) but all had normal responses to 0.25 mg of Cortrosyn stimulation (cortisol > 18 µg/dL). A clinical study was conducted to assess the safety of Derma-Smoothe/FS, which contains refined peanut oil, on subjects with known peanut allergies. The study enrolled 13 patients with atopic dermatitis, 6 to 17 years of age. Of the 13 patients, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The study evaluated the responses to both prick test and patch test utilizing peanut oil NF, Derma-Smoothe/FS® and histamine/saline controls, on the 13 individuals . These subjects were also treated with Derma-Smoothe/FS® twice daily for 7 days . Prick test and patch test results for all 13 patients were negative to Derma-Smoothe/FS® and the refined peanut oil. One of the 9 peanut-sensitive patients experienced an exacerbation of atopic dermatitis after 5 days of Derma-Smoothe/FS®. Importantly, the bulk peanut oil NF, used in Derma- Smoothe/FS® is heated at 475° F for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins. INDICATION AND USAGE Derma-Smoothe/FS® is a low to medium potency corticosteroid indicated: In adult patients for the treatment of atopic dermatitis. (Body Oil) In pediatric patients 2 years and older with moderate to severe atopic dermatitis (Body Oil). It may be used for up to 4 weeks. CONTRAINDICATIONS Derma-Smoothe/FS® is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. This product contains refined peanut oil NF (see PRECAUTIONS section). PRECAUTIONS General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic- pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 6 withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Infrequently, signs and symptoms of glucocorticoid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS-Pediatric use) Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than noting a clinical exacerbation, which may occur with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic testing. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma-Smoothe/FS® (see CLINICAL STUDIES section). If wheal and flare type reactions (which may be limited to pruritus) or other manifestations of hypersensitivity develop, Derma-Smoothe/FS® should be discontinued immediately and appropriate therapy instituted. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Derma-Smoothe/FS® should be discontinued until the infection has been adequately controlled. Derma-Smoothe/FS® is formulated with 48% refined peanut oil NF. Peanut oil used in this product is routinely tested for peanut proteins using a sandwich enzyme-linked immunosorbent assay test (S- ELISA) kit, which can detect peanut proteins to as low as 2.5 parts per million (ppm). Physicians should use caution in prescribing Derma-Smoothe/FS® for peanut-sensitive individuals. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. In case of contact, wash eyes liberally with water. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should promptly report to their physician any worsening of their skin condition. 4. Parents of pediatric patients should be advised not to use Derma-Smoothe/FS® in the treatment of diaper dermatitis. Derma-Smoothe/FS® should not be applied to the diaper area as diapers or plastic pants may constitute occlusive dressing. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 7 5. This medication should not be used on the face, underarm, or groin unless directed by the physician. 6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician. Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH stimulation test A.M. plasma cortisol test Urinary free cortisol test Carcinogenesis, mutagenesis, and impairment of fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of Derma-Smoothe/FS®. Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide, the active ingredient in Derma-Smoothe/FS®. Some corticosteroids have been found to be genotoxic in various genotoxicity tests (i.e. the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay). Pregnancy: Teratogenic effects: Pregnancy category C: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from Derma-Smoothe/FS®. Therefore, Derma-Smoothe/FS® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Derma-Smoothe/FS® is administered to a nursing woman. Pediatric Use: Derma-Smoothe/FS® may be used twice daily for up to 4 weeks in pediatric patients 2 years and older with moderate to severe atopic dermatitis. Derma-Smoothe/FS® should not be applied to the diaper area. Application to intertriginous areas should be avoided due to the increased possibility of local adverse events such as striae, atrophy, and telangiectasia, which may be irreversible. The smallest amount of drug needed to cover the affected areas should be applied. Long term safety in the pediatric population has not been established. Derma-Smoothe/FS® is not recommended for use on the face (see ADVERSE REACTIONS section). Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 8 syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. (SEE PRECAUTIONS). HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Derma-Smoothe/FS® is formulated with 48% refined peanut oil NF, in which peanut protein is not detectable at 2.5 ppm. Physicians should use caution in prescribing Derma-Smoothe/FS® for peanut sensitive individuals. ADVERSE REACTIONS The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma- Smoothe/FS®. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 9 A post marketing (open-label) safety study was conducted in 58 children to evaluate the local safety of Derma-Smoothe/FS when applied twice daily for 4 weeks to the face in children (2 to 12 years) with moderate to severe atopic dermatitis (see table of Incidence of Adverse Events). Incidence of Adverse Events (%) N=58 Adverse Event (AE)* # of patients (%) Day 14 Day 28 Day 56* Any AE 15 (25.9) 6 (10.3) 7 (12.1) 7 (12.1) Telangiectasia 5 (8.6) 3 (5.2) 4 (6.9) 2 (3.5) Erythema 3 (5.2) 3 (5.2) Itching 3 (5.2) 3 (5.2) Irritation 3 (5.2) 3 (5.2) Burning 3 (5.2) 3 (5.2) Hypopigmentation 2 (3.5) 2 (3.5) Shiny skin 1 (1.7) 1 (1.7) Secondary atopic dermatitis 1 (1.7) 1 (1.7) Papules and pustules 1 (1.7) 1 (1.7) Keratosis pilaris 1 (1.7) 1 (1.7) Folliculitis 1 (1.7) 1 (1.7) Facial herpes simplex 1 (1.7) 1 (1.7) Acneiform eruption 1 (1.7) 1 (1.7) Ear infection 1 (1.7) 1 (1.7) The number of individual adverse events reported does not necessarily reflect the number of individual subjects, since one subject could have multiple reportings of an adverse event. End of Treatment *Four Weeks Post Treatment OVERDOSAGE Topically applied Derma-Smoothe/FS® can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Derma-Smoothe/FS® for atopic dermatitis in adults (Body Oil): For the treatment of atopic dermatitis, Derma-Smoothe/FS® should be applied as a thin film to the affected area three times daily. Derma-Smoothe/FS® for atopic dermatitis in pediatric patients 2 years and older (Body Oil): Moisten skin. Apply Derma-Smoothe/FS® as a thin film to the affected areas twice daily for no longer than four weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 10 HOW SUPPLIED Derma-Smoothe/FS® is supplied in bottles containing 4 fluid ounces. It is labeled as Body Oil (NDC # 28105-150-04). Keep tightly closed. Store at 25° C (68° to 77° F); excursions permitted to 15E-30E C (59E-86EF.) [see USP Controlled Room Temperature] CAUTION: Rx only MANUFACTURED AND DISTRIBUTED BY: Hill Laboratories, Inc. Sanford, Florida 32773 Rev. CODE xxxxx Date: 1/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 11 CONTAINER LABEL Left side of Container Label NDC 28105-150-04 Rx Only DERMA-SMOOTHE/FS ® Fluocinolone Acetonide 0.01% Topical Oil BODY OIL FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC or INTRAVAGINAL USE SHAKE WELL BEFORE USE Net Contents 118.28 mL (4 fl. oz.) SINCE 1943 HILL DERMACEUTICALS, INC. SANFORD, FLORIDA 32773 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 12 Right Side of Container Label Keep Out the Reach of Children FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE DOSAGE AND ADMINISTRATION: Atopic dermatitis in pediatric patients 2 years and older: Moisten skin. Apply Derma-Smoothe/FS® as a thin film to the affected areas twice daily for up to 4 weeks. Atopic eczema / dermatitis in adults: Moisten skin. Apply Derma-Smoothe/FS® as a thin film to the affected areas three times daily. DO NOT USE WITH OCCLUSION SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Contains: Fluocinolone Acetonide (0.01%), Isopropyl Alcohol (1.6%), in a base containing Refined Peanut Oil NF, Mineral Oil, Isopropyl Myristate, Oleth-2, Cream Fragrance and Balsam Pine. Storage: Keep tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [ see USP Controlled Room Temperature] Lot No. Exp. Date Manufactured and Distributed by: HILL DERMACEUTICALS, INC. Sanford, Florida 32773 Manufactured by: HILL LABORATORIES, INC. CODE No. XXXXXXX Sanford, Florida 32773 Rev. XX/XX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 13 CARTON LABEL Front and Back of Box NDC 28105-150-04 Rx only DERMA-SMOOTHE/FS® Fluocinolone Acetonide 0.01% Topical Oil BODY OIL FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE SHAKE WELL BEFORE USE Net Contents 118.28 mL (4 fl. oz.) SINCE 1949 HILL DERMACEUTICALS, INC. SANFORD, FLORIDA 32773 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 14 SIDE PANEL 1 Contains: Fluocinolone Acetonide (0.01%), Isopropyl Alcohol (1.6%), in a base containing Refined Peanut Oil NF, Mineral Oil, Isopropyl Myristate, Oleth-2, Cream Fragrance and Balsam Pine. Storage: Keep tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [ see USP Controlled Room Temperature] Keep Out of Reach of Children FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE CODE NO. XXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 15 SIDE PANEL 2 DOSAGE AND ADMINISTRATION: Atopic dermatitis in pediatric patients 2 years and older: Moisten skin. Apply Derma- Smoothe/FS® as a thin film to the affected areas twice daily for up to 4 weeks. Atopic eczema / dermatitis in adults: Moisten skin. Apply Derma-Smoothe/FS® as a thin film to the affected areas three times daily. DO NOT USE WITH OCCLUSION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. Manufactured and Distributed by: Manufactured by: HILL DERMACEUTICALS, INC. HILL LABORATORIES, INC. Sanford, Florida 32773 Sanford, Florida 32773 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 16 Bottom Panel Lot No: Exp. Date: Rev. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 17 Derma-Smoothe/FS® fluocinolone acetonide Topical Oil, 0.01% (Scalp Oil) For Topical Use Only- NDC 28105-149-04 Not for Oral, Ophthalmic, or Intravaginal Use DESCRIPTION Derma-Smoothe/FS® Topical Oil contains fluocinolone acetonide {(6α, 11β, 16α)-6,9-difluoro-11,21- dihydroxy-16,17[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione, cyclic 16,17 acetal with acetone}, a synthetic corticosteroid for topical dermatologic use. This formulation is also marketed as Derma-Smoothe/FS® 0.01%, fluocinolone acetonide for use as body oil for atopic dermatitis in adults and for moderate to severe atopic dermatitis in pediatric patients 2 years and older and as fluocinone acetonide oil, 0.01% for chronic eczematous external otitis. Chemically, fluocinolone acetonide is C24 H30 F2 O6. It has the following structural formula: Fluocinolone acetonide in Derma-Smoothe/FS® has a molecular weight of 452.50. It is a white crystalline powder that is odorless, stable in light, and melts at 270°C with decomposition; soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water. Each gram of Derma-Smoothe/FS® contains approximately 0.11 mg of fluocinolone acetonide in a blend of oils, which contains isopropyl alcohol, isopropyl myristate, light mineral oil, oleth-2, refined peanut oil NF and fragrances. Each packaged product contains 2 shower caps. The shower cap is made of low density polyethylene material with rubber elastic. CLINICAL PHARMACOLOGY Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 18 Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusion of topical corticosteroids can enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Also, inflammation and/or other disease processes in the skin can increase percutaneous absorption. Derma-Smoothe/FS® is in the low to medium range of potency as compared with other topical corticosteroids. CLINICAL STUDIES In a vehicle-controlled study for the treatment of psoriasis of the scalp in adults, after 21 days of treatment, 60% of patients on active treatment and 21% of patients on the drug vehicle had excellent to cleared clinical response. Open-label safety studies on 33 children (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis, and baseline body surface area involvement greater than 75% in 18 patients, and 50% to 75% in 15 patients, were treated with Derma-Smoothe/FS® twice daily for 4 weeks. Morning pre-stimulation cortisol level and post-Cortrosyn stimulation cortisol level were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal: cortisol > 7µg/dL) but all had normal responses to 0.25 mg of Cortrosyn stimulation (cortisol > 18 µg/dL). A clinical study was conducted to assess the safety of Derma-Smoothe/FS, which contains refined peanut oil, on subjects with known peanut allergies. The study enrolled 13 patients with atopic dermatitis, 6 to 17 years of age. Of the 13 patients, 9 were Radioallergosorbent Test (RAST) positive to peanuts and 4 had no peanut sensitivity (controls). The study evaluated the responses to both prick test and patch test utilizing peanut oil NF, Derma-Smoothe/FS® and histamine/saline controls, on the 13 individuals. These subjects were also treated with Derma-Smoothe/FS® twice daily for 7 days. Prick test and patch test results for all 13 patients were negative to Derma-Smoothe/FS® and the refined peanut oil. One of the 9 peanut-sensitive patients experienced an exacerbation of atopic dermatitis after 5 days of Derma-Smoothe/FS®. Importantly, the bulk peanut oil NF, used in Derma- Smoothe/FS® is heated at 475° F for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins. INDICATION AND USAGE Derma-Smoothe/FS® is a low to medium potency corticosteroid indicated: In adult patients for the treatment of psoriasis of the scalp (Scalp Oil). In pediatric patients 2 years and older with moderate to severe atopic dermatitis. It may be used for up to 4 weeks. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 19 CONTRAINDICATIONS Derma-Smoothe/FS® is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. This product contains refined peanut oil NF (see PRECAUTIONS section). PRECAUTIONS General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic- pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Infrequently, signs and symptoms of glucocorticoid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than noting a clinical exacerbation, which may occur with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic testing. One peanut-sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma-Smoothe/FS® (see CLINICAL STUDIES section). If wheal and flare type reactions (which may be limited to pruritus) or other manifestations of hypersensitivity develop, Derma-Smoothe/FS® should be discontinued immediately and appropriate therapy instituted. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Derma-Smoothe/FS® should be discontinued until the infection has been adequately controlled. Derma-Smoothe/FS® is formulated with 48% refined peanut oil NF. Peanut oil used in this product is routinely tested for peanut proteins using a sandwich enzyme-linked immunosorbent assay test (S- ELISA) kit, which can detect peanut proteins to as low as 2.5 parts per million (ppm). Physicians should use caution in prescribing Derma-Smoothe/FS® for peanut-sensitive individuals. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 20 Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. In case of contact, wash eyes liberally with water. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should promptly report to their physician any worsening of their skin condition. 4. Parents of pediatric patients should be advised not to use Derma-Smoothe/FS® in the treatment of diaper dermatitis. Derma-Smoothe/FS® should not be applied to the diaper area as diapers or plastic pants may constitute occlusive dressing. 5. This medication should not be used on the face, underarm, or groin unless directed by the physician. 6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician. Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH stimulation test A.M. plasma cortisol test Urinary free cortisol test Carcinogenesis, mutagenesis, and impairment of fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of Derma-Smoothe/FS®. Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide, the active ingredient in Derma-Smoothe/FS®. Some corticosteroids have been found to be genotoxic in various genotoxicity tests (i.e. the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay). Pregnancy: Teratogenic effects: Pregnancy category C: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from Derma-Smoothe/FS®. Therefore, Derma-Smoothe/FS® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Derma-Smoothe/FS® is administered to a nursing woman. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 21 Pediatric Use: Derma-Smoothe/FS® may be used twice daily for up to 4 weeks in pediatric patients 2 years and older with moderate to severe atopic dermatitis . Derma-Smoothe/FS® should not be applied to the diaper area. Application to intertriginous areas should be avoided due to the increased possibility of local adverse events such as striae, atrophy, and telangiectasia, which may be irreversible. The smallest amount of drug needed to cover the affected areas should be applied. Long term safety in the pediatric population has not been established. Derma-Smoothe/FS® is not recommended for use on the face (see ADVERSE REACTIONS section). Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. (SEE PRECAUTIONS). HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Derma-Smoothe/FS® is formulated with 48% refined peanut oil NF, in which peanut protein is not detectable at 2.5 ppm. Physicians should use caution in prescribing Derma-Smoothe/FS® for peanut sensitive individuals. ADVERSE REACTIONS The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. One peanut sensitive child experienced a flare of his atopic dermatitis after 5 days of twice daily treatment with Derma- Smoothe/FS®. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 22 A post marketing (open-label) safety study was conducted in 58 children to evaluate the local safety of Derma-Smoothe/FS when applied twice daily for 4 weeks to the face in children (2 to 12 years) with moderate to severe atopic dermatitis (see table of Incidence of Adverse Events). Incidence of Adverse Events (%) N=58 Adverse Event (AE) # of patients (%) Day 14 Day 28 Day 56* Any AE 15 (25.9) 6 (10.3) 7 (12.1) 7 (12.1) Telangiectasia 5 (8.6) 3 (5.2) 4 (6.9) 2 (3.5) Erythema 3 (5.2) 3 (5.2) Itching 3 (5.2) 3 (5.2) Irritation 3 (5.2) 3 (5.2) Burning 3 (5.2) 3 (5.2) Hypopigmentation 2 (3.5) 2 (3.5) Shiny skin 1 (1.7) 1 (1.7) Secondary atopic dermatitis 1 (1.7) 1 (1.7) Papules and pustules 1 (1.7) 1 (1.7) Keratosis pilaris 1 (1.7) 1 (1.7) Folliculitis 1 (1.7) 1 (1.7) Facial herpes simplex 1 (1.7) 1 (1.7) Acneiform eruption 1 (1.7) 1 (1.7) Ear infection 1 (1.7) 1 (1.7) The number of individual adverse events reported does not necessarily reflect the number of individual subjects, since one subject could have multiple reportings of an adverse event. End of Treatment **Four Weeks Post Treatment OVERDOSAGE Topically applied Derma-Smoothe/FS® can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Derma-Smoothe/FS® for scalp psoriasis in adults (Scalp Oil): For the treatment of scalp psoriasis, wet or dampen hair and scalp thoroughly. Apply a thin film of Derma-Smoothe/FS® on the scalp, massage well and cover scalp with the supplied shower cap. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 23 HOW SUPPLIED Derma-Smoothe/FS® is supplied in bottles containing 4 fluid ounces. It is labeled as Scalp Oil (NDC # 28105-149-04). Scalp Oil is supplied with 2 shower caps. Keep tightly closed. Store at 25° C (68° to 77° F); excursions permitted to 15E-30E C (59E-86EF.) [see USP Controlled Room Temperature] CAUTION: Rx only MANUFACTURED BY AND DISTRIBUTED BY: Hill Laboratories, Inc. Sanford, Florida 32773 Rev. CODE xxxxx Date: 1/04 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 24 CARTON LABEL DERMA-SMOOTHE/FS SCALP OIL Front and Back of Carton NDC 28105-149-04 RX only DERMA-SMOOTHE/FS® Fluocinolone Acetonide 0.01% Topical Oil (SCALP OIL) FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE SHAKE WELL BEFORE USE Net Wt. 4 fl. oz. (118.28 mL) Since 1943 HILL Dermaceuticals, Inc Sanford, Florida 32773 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 25 Left Side of Carton Contains: Fluocinolone Acetonide (0.01%), Isopropyl Alcohol (1.6%), in a base containing Refined Peanut Oil NF, Mineral Oil, Isopropyl Myristate, Oleth-2, Cream Fragrance and Balsam Pine. Contents of Package: 4 fl. oz. bottle 2 shower caps Storage: Keep tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] Keep Out of Reach of Children FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE CODE NO XXXXXXX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 26 Right Side of Carton DOSAGE AND ADMINISTRATION: For the treatment of scalp psoriasis, wet or dampen hair and scalp thoroughly. Apply a thin film of Derma-Smoothe/FS® on the scalp, massage well and cover scalp with one of the supplied shower caps. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. Manufactured and Distributed By: HILL DERMACEUTICALS, INC. Sanford, Florida 32773 Manufactured By: HILL LABORATORIES, INC. Sanford, Florida 32773 Product Bar Code Here This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 27 Bottom Flap of Carton Lot No. Exp. Date: REV. XX/XX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 28 CONTAINER LABEL DERMA-SMOOTHE/FS SCALP OIL LEFT SIDE NDC 28105-149-04 Rx only DERMA-SMOOTHE/FS® Fluocinolone Acetonide 0.01% Topical Oil (SCALP OIL) FOR TOPICAL USE ONLY NOT FOR ORAL, OPHTHALMIC, or INTRAVAGINAL USE SHAKE WELL BEFORE USE Net Wt. 4 fl. oz. (118.28 mL) Since 1943 Hill Dermaceuticals, Inc. Sanford, Florida 32773 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 29 RIGHT SIDE Keep Out of Reach of Children FOR TOPICAL USE ONLY Not For Oral, Ophthalmic, or Intravaginal Use Dosage and Administration: For the treatment of scalp psoriasis, wet or dampen hair and scalp thoroughly. Apply a thin film of Derma-Smoothe/FS® on the scalp, massage well and cover scalp with one of the supplied shower caps. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly. See package Insert for Full Prescribing Information. Contains: Fluocinolone Acetonide (0.01%), Isopropyl Alcohol (1.6%), in a base containing Refined Peanut Oil NF, Mineral Oil, Isopropyl Myristate, Oleth-2, Cream Fragrance and Balsam Pine. Contents of Package: 4 fl. oz. bottle / 2 shower caps Storage: Keep tightly closed. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] Lot No.: Exp. Date: Manufactuerd and Distributed By: HILL DERMACEUTICALS, INC. Sanford, Florida 32773 Manufactured By: HILL LABORATORIES, INC. Code: XXXXXXX Sanford, Florida 32773 Rev. XX/XX This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 30 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19-452/S-016/S-019 & S-020 Page 31 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.956530	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019452s016,019,020lbl.pdf', 'application_number': 19452, 'submission_type': 'SUPPL ', 'submission_number': 16}
11,507	NDA 19452/S-017 Page 4 Derma-Smoothe/FS   (fluocinolone acetonide topical oil) Topical Oil, 0.01% For Dermatologic Use Only- NDC 28105-149-04 Not for Ophthalmic Use- DESCRIPTION Derma-Smoothe/FS contains fluocinolone acetonide {(6α, 11β, 16α)-6,9-difluoro-11,21-dihydroxy- 16,17[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione, cyclic 16,17 acetal with acetone}, a synthetic corticosteroid for topical dermatologic use. Chemically, fluocinolone acetonide is C24 H30 F2 O6. It has the following structural formula: Fluocinolone acetonide in Derma-Smoothe/FS has a molecular weight of 452.50. It is a white crystalline powder that is odorless, stable in light, and melts at 270°C with decomposition; soluble in alcohol, acetone and methanol; slightly soluble in chloroform; insoluble in water. Each gram of Derma-Smoothe/FS contains approximately 0.11 mg of fluocinolone acetonide in a blend of oils, which contains isopropyl alcohol, isopropyl myristate, light mineral oil, oleth-2, refined peanut oil NF and fragrances. CLINICAL PHARMACOLOGY Like other topical corticosteroids, fluocinolone acetonide has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Occlusion of topical corticosteroids can enhance penetration. Topical corticosteroids can be absorbed from normal intact skin. Also, inflammation and/or other disease processes in the skin can increase percutaneous absorption. Derma-Smoothe/FS is in the low to medium range of potency as compared with other topical This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19452/S-017 Page 5 corticosteroids. CLINICAL STUDIES In a vehicle-controlled study for the treatment of psoriasis of the scalp in adults, after 21 days of treatment, 60% of patients on active treatment and 21% of patients on the drug vehicle had excellent to cleared clinical response. Open-label safety studies on 33 children (20 subjects ages 2 to 6 years, 13 subjects ages 7 to 12 years) with moderate to severe stable atopic dermatitis, and baseline body surface area involvement greater than 75% in 18 patients, and 50% to 75% in 15 patients, were treated with Derma-Smoothe/FS twice daily for 4 weeks. Morning pre-stimulation cortisol level and post-Cortrosyn stimulation cortisol level were obtained in each subject at the beginning of the trial and at the end of 4 weeks of treatment. At the end of treatment, 4 out of 18 subjects aged 2 to 5 years showed low pre-stimulation cortisol levels (3.2 to 6.6 µg/dL; normal: cortisol > 7µg/dL) but all had normal responses to 0.25 mg of Cortrosyn stimulation (cortisol > 18 µg/dL). A clinical study evaluated the response of peanut-sensitive and peanut-insensitive children to both Prick test and Patch test utilizing peanut oil NF, Derma-Smoothe/FS and histamine/saline controls, on 13 individuals, 9 of whom were RAST-test positive for peanut allergens prior to the trial. These subjects were also treated with Derma-Smoothe/FS twice daily for 2 weeks. Prick test and patch test results for all 13 patients were negative. Importantly, the bulk peanut oil NF, used in Derma-Smoothe/FS is heated at 475° F for at least 15 minutes, which should provide for adequate decomposition of allergenic proteins. INDICATION AND USAGE Derma-Smoothe/FS is a low to medium potency corticosteroid indicated: In adult patients for the treatment of atopic dermatitis or psoriasis of the scalp. In pediatric patients 2 years and older with moderate to severe atopic dermatitis. It may be used for up to 4 weeks. CONTRAINDICATIONS Derma-Smoothe/FS is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. This product contains refined peanut oil NF (see PRECAUTIONS section). PRECAUTIONS General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary- adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19452/S-017 Page 6 A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Infrequently, signs and symptoms of glucocorticoid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS-Pediatric use) Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than noting a clinical exacerbation, which may occur with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic testing. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Derma-Smoothe/FS should be discontinued until the infection has been adequately controlled. If wheal and flare type reactions (which may be limited to pruritus) or other manifestations of hypersensitivity develop, Derma-Smoothe/FS should be discontinued immediately and appropriate therapy instituted. One peanut sensitive child experienced a flare of his atopic dermatitis during two weeks of twice daily treatment with Derma-Smoothe/FS. Derma-Smoothe/FS is formulated with 48% refined peanut oil NF. Peanut oil used in this product is routinely tested for peanut proteins using a sandwich enzyme-linked immunosorbent assay test (S-ELISA) kit, which can detect peanut proteins to as low as 2.5 parts per million (ppm). Physicians should use caution in prescribing Derma-Smoothe/FS for peanut-sensitive children. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. In case of contact, wash eyes liberally with water. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should promptly report to their physician any worsening of their skin condition. 4. Parents of pediatric patients should be advised not to use Derma-Smoothe/FS in the treatment of diaper dermatitis. Derma-Smoothe/FS should not be applied to the diaper area as diapers or plastic pants may constitute occlusive dressing. 5. This medication should not be used on the face, underarm, or groin unless directed by the physician. 6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19452/S-017 Page 7 improvement is seen within 2 weeks, contact the physician. Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH stimulation test A.M. plasma cortisol test Urinary free cortisol test Carcinogenesis, mutagenesis, and impairment of fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of Derma-Smoothe/FS. Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide, the active ingredient in Derma-Smoothe/FS. Some corticosteroids have been found to be genotoxic in various genotoxicity tests (i.e. the in vitro human peripheral blood lymphocyte chromosome aberration assay with metabolic activation, the in vivo mouse bone marrow micronucleus assay, the Chinese hamster micronucleus test and the in vitro mouse lymphoma gene mutation assay). Pregnancy: Teratogenic effects: Pregnancy category C: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from Derma- Smoothe/FS. Therefore, Derma-Smoothe/FS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Derma-Smoothe/FS is administered to a nursing woman. Pediatric Use: Derma-Smoothe/FS may be used in pediatric patients 2 years and older with moderate to severe atopic dermatitis when used twice daily for no longer than four weeks. Derma-Smoothe/FS should not be applied to the face or diaper area. Application to intertriginous areas should be avoided due to the increased possibility of local adverse events such as striae, atrophy, and telangiectasia, which may be irreversible. The smallest amount of drug needed to cover the affected areas should be applied. Long term safety in the pediatric population has not been established. Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. (SEE PRECAUTIONS). This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19452/S-017 Page 8 HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Derma-Smoothe/FS is formulated with 48% refined peanut oil NF, in which peanut protein in not detectable at 2.5 ppm. Physicians should use caution in prescribing Derma-Smoothe/FS for peanut sensitive individuals. (See PRECAUTIONS-Pediatric Use) ADVERSE REACTIONS The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. One peanut sensitive child experienced a flare of his atopic dermatitis during two weeks of twice daily treatment with Derma- Smoothe/FS. OVERDOSAGE Topically applied Derma-Smoothe/FS can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Atopic dermatitis in adults: For the treatment of atopic dermatitis, Derma-Smoothe/FS should be applied as a thin film to the affected area three times daily. Scalp psoriasis in adults: For the treatment of scalp psoriasis, wet or dampen hair and scalp thoroughly. Apply a thin film of Derma- Smoothe/FS on the scalp, massage well and cover scalp with the supplied shower cap. Leave on overnight or for a minimum of 4 hours before washing off. Wash hair with regular shampoo and rinse thoroughly. Atopic dermatitis in pediatric patients 2 years and older: Moisten skin. Apply Derma-Smoothe/FS as a thin film to the affected areas twice daily for no longer than four weeks. HOW SUPPLIED Derma-Smoothe/FS is supplied in bottles containing 4 fluid ounces (NDC # 28105-149-04). Store between 20° -25° C (68° to 77° F) in tightly closed containers. CAUTION: Rx only This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDA 19452/S-017 Page 9 MANUFACTURED BY: DISTRIBUTED BY: Hill Laboratories, Inc. Hill Dermaceuticals, Inc. Sanford, Florida 32773 Sanford, Florida 32773 Rev. CODE xxxxx Date: 10/03/01 --------------------------------------------------------------------- ----------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------- ----------------------------------- /s/ --------------------- Jonathan Wilkin 10/10/01 12:42:31 PM This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:24.981637	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19452s17lbl.pdf', 'application_number': 19452, 'submission_type': 'SUPPL ', 'submission_number': 17}
11,508	NDAs 19-462, 19-527, 20-752 Page 3 PEPCID® (FAMOTIDINE) TABLETS PEPCID® (FAMOTIDINE) FOR ORAL SUSPENSION PEPCID RPD® (FAMOTIDINE) ORALLY DISINTEGRATING TABLETS DESCRIPTION The active ingredient in PEPCID* (famotidine) is a histamine H2-receptor antagonist. Famotidine is N′- (aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine is C8H15N7O2S3 and its molecular weight is 337.43. Its structural formula is: Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol. Each tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, corn starch, talc, and titanium dioxide. Each Orally Disintegrating Tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive ingredients: aspartame, mint flavor, gelatin, mannitol, red ferric oxide, and xanthan gum. Each 5 mL of the oral suspension when prepared as directed contains 40 mg of famotidine and the following inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose and xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and sodium propylparaben 0.02%. CLINICAL PHARMACOLOGY IN ADULTS GI Effects PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by PEPCID, while changes in pepsin secretion are proportional to volume output. In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours. Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of PEPCID was raised to about 5. * Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1986, 1988, 1991, 1995, 1996 All rights reserved This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 4 PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by PEPCID. Other Effects Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with PEPCID. Pharmacokinetics PEPCID is incompletely absorbed. The bioavailability of oral doses is 40-45%. PEPCID Tablets, PEPCID for Oral Suspension and PEPCID RPD Orally Disintegrating Tablets are bioequivalent. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. PEPCID undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound. PEPCID has an elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide. There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half- life of PEPCID may exceed 20 hours and adjustment of dose or dosing intervals may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION). In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID. Clinical Studies Duodenal Ulcer In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with PEPCID 40 mg h.s. were healed by week 4. Table 1 Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers PEPCID 40 mg h.s. (N = 89) PEPCID 20 mg b.i.d. (N = 84) Placebo h.s. (N = 97) Week 2 Week 4 32% 70% 38% 67% 17% 31% Statistically significantly different than placebo (p<0.001) Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with PEPCID had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers. In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients receiving placebo. Long-Term Maintenance Treatment of Duodenal Ulcers PEPCID, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an international study where the cumulative observed ulcer This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 5 incidence within 12 months in the 307 patients treated with PEPCID was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01). Gastric Ulcer In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the PEPCID and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with PEPCID was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy. Table 2 Patients with Endoscopically Confirmed Healed Gastric Ulcers U.S. Study International Study PEPCID 40 mg h.s. (N=74) Placebo h.s. (N=75) PEPCID 40 mg h.s. (N=149) Placebo h.s. (N=145) Week 4 Week 6 Week 8 45% †66% 78% 39% 44% 64% †47% †65% †80% 31% 46% 54% *,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively) Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving PEPCID than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8). Gastroesophageal Reflux Disease (GERD) Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20 mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms (Table 3). Table 3 % Successful Symptomatic Outcome PEPCID 20 mg b.i.d. (N=154) PEPCID 40 mg h.s. (N=149) Placebo (N=73) Week 6 82†† 69 62 †† p≤0.01 vs Placebo By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking PEPCID 20 mg b.i.d. compared to placebo (p≤0.01). Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d. showed a significantly greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4). Table 4 % Endoscopic Healing - U.S. Study PEPCID 40 mg b.i.d. (N=127) PEPCID 20 mg b.i.d. (N=125) Placebo (N=66) Week 6 Week 12 48†††,‡‡ 69†††,‡ 32 54††† 18 29 ††† p≤0.01 vs Placebo ‡ p≤0.05 vs PEPCID 20 mg b.i.d. ‡‡ p≤0.01 vs PEPCID 20 mg b.i.d. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 6 As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were statistically significant. In the international study, when PEPCID 40 mg p.o. b.i.d., was compared to ranitidine 150 mg p.o. b.i.d., a statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12 (Table 5). There was, however, no significant difference among treatments in symptom relief. Table 5 % Endoscopic Healing - International Study PEPCID 40 mg b.i.d. (N=175) PEPCID 20 mg b.i.d. (N=93) Ranitidine 150 mg b.i.d. (N=172) Week 6 Week 12 48 71‡‡‡ 52 68 42 60 ‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d. Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. PEPCID was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug. CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS Pharmacokinetics Table 6 presents pharmacokinetic data from published studies of small numbers of pediatric patients given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose). Table 6 Pharmacokinetic Parametersa of Intravenous Famotidine Age (N=number of patients) Area Under the Curve (AUC) (ng-hr/mL) Total Clearance (Cl) (L/hr/kg) Volume of Distribution (Vd) (L/kg) Elimination Half-life (T1/2) (hours) 1-11 yrs (N=20) 1089 ± 834 0.54 ± 0.34 2.07 ± 1.49 3.38 ± 2.60 11-15 yrs (N=6) 1140 ± 320 0.48 ± 0.14 1.5 ± 0.4 2.3 ± 0.4 Adult (N=16) 1726b 0.39 ± 0.14 1.3 ± 0.2 2.83 ± 0.99 aValues are presented as means ± SD unless indicated otherwise. bMean value only. Values of pharmacokinetic parameters for pediatric patients, ages 1-15 years, are comparable to those obtained for adults. Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved an AUC of 580 ± 60 ng-hr/mL in pediatric patients 11-15 years of age compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally. Pharmacodynamics Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults (Table 7). Table 7 Pharmacodynamics of famotidine using the sigmoid Emax model EC50 (ng/mL) Pediatric Patients 26 ± 13 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 7 Data from one study a) healthy adult subjects 26.5 ± 10.3 b) adult patients with upper GI bleeding 18.7 ± 10.8 *Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD. Four published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows: Table 8 Dosage Route Effect a Number of Patients 0.3 mg/kg, single dose I.V. gastric pH >3.5 for 8.7 ± 4.7 b hours 6 0.4-0.8 mg/kg I.V. gastric pH >4 for 6-9 hours 18 0.5 mg/kg, single dose I.V. a >2 pH unit increase above baseline in gastric pH for >8 hours 9 0.5 mg/kg b.i.d. I.V. gastric pH >5 for 13.5 ± 1.8 b hours 4 0.5 mg/kg b.i.d. oral gastric pH >5 for 5.0 ± 1.1 b hours 4 avalues reported in published literature. bMeans ± SD. INDICATIONS AND USAGE PEPCID is indicated in: 1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks. 2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year. 3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8 weeks. 4. Short term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies). PEPCID is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies). 5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies). CONTRAINDICATIONS Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been observed. Therefore, PEPCID should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists. PRECAUTIONS General Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy. Patients with Severe Renal Insufficiency Longer intervals between doses or lower doses may need to be used in patients with severe renal insufficiency (creatinine clearance <10 mL/min) to adjust for the longer elimination half-life of famotidine. (See CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION.) However, currently, no drug-related toxicity has been found with high plasma concentrations of famotidine. Information for Patients The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each use. Unused constituted oral suspension should be discarded after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 8 Patients should be instructed to leave the PEPCID RPD Orally Disintegrating Tablet in the unopened package until the time of use. Patients should then open the tablet blister pack with dry hands, place the tablet on the tongue to dissolve and be swallowed with saliva. No water is needed for taking the tablet. Phenylketonurics: Phenylketonuric patients should be informed that PEPCID RPD contains phenylalanine 1.05 mg per 20 mg orally disintegrating tablet and 2.10 mg per 40 mg orally disintegrating tablet. Drug Interactions No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for PEPCID. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected. Pregnancy Pregnancy Category B Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from PEPCID, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Patients Use of PEPCID in pediatric patients 1-16 years of age is supported by evidence from adequate and well- controlled studies of PEPCID in adults, and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest a starting dose for pediatric patients 1-16 years of age as follows: Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day. Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d. While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 9 (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations. No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age. Geriatric Use Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of severe renal impairment is necessary (see PRECAUTIONS, Patients with Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Severe Renal Insufficiency). ADVERSE REACTIONS The adverse reactions listed below have been reported during domestic and international clinical trials in approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to placebo, the incidence of adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime, was similar to that in the placebo group. The following adverse reactions have been reported to occur in more than 1% of patients on therapy with PEPCID in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%) and diarrhea (1.7%). The following other adverse reactions have been reported infrequently in clinical trials or since the drug was marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the adverse reactions are listed in order of decreasing severity: Body as a Whole: fever, asthenia, fatigue Cardiovascular: arrhythmia, AV block, palpitation Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dry mouth Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence Respiratory: bronchospasm Skin: toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing Special Senses: tinnitus, taste disorder Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled clinical trials, the incidences were not greater than those seen with placebo. The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension and PEPCID RPD Orally Disintegrating Tablets. OVERDOSAGE There is no experience to date with deliberate overdosage. Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 10 The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse. DOSAGE AND ADMINISTRATION Duodenal Ulcer Acute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at bedtime. Most patients heal within 4 weeks; there is rarely reason to use PEPCID at full dosage for longer than 6 to 8 weeks. A regimen of 20 mg b.i.d. is also effective. Maintenance Therapy: The recommended adult oral dose is 20 mg once a day at bedtime. Benign Gastric Ulcer Acute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at bedtime. Gastroesophageal Reflux Disease (GERD) The recommended oral dosage for treatment of adult patients with symptoms of GERD is 20 mg b.i.d. for up to 6 weeks. The recommended oral dosage for the treatment of adult patients with esophagitis including erosions and ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies). Dosage for Pediatric Patients See PRECAUTIONS, Pediatric Patients. The studies described in PRECAUTIONS, Pediatric Patients suggest the following starting doses in pediatric patients 1-16 years of age: Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day. Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d. While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations. No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age. Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome. Oral Suspension PEPCID for Oral Suspension may be substituted for PEPCID Tablets in any of the above indications. Each five mL contains 40 mg of famotidine after constitution of the powder with 46 mL of Purified Water as directed. Directions for Preparing PEPCID for Oral Suspension Prepare suspension at time of dispensing. Slowly add 46 mL of Purified Water. Shake vigorously for 5-10 seconds immediately after adding the water and immediately before use. Stability of PEPCID for Oral Suspension Unused constituted oral suspension should be discarded after 30 days. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 11 Orally Disintegrating Tablets PEPCID RPD Orally Disintegrating Tablets may be substituted for PEPCID Tablets in any of the above indications at the same recommended dosages. PEPCID RPD Orally Disintegrating Tablets rapidly disintegrate on the tongue. No water is needed for taking the tablet. Patients should be instructed to open the tablet blister pack with dry hands, place the tablet on the tongue to disintegrate and be swallowed with saliva. Concomitant Use of Antacids Antacids may be given concomitantly if needed. Dosage Adjustment for Patients with Severe Renal Insufficiency In adult patients with severe renal insufficiency, i.e., with a creatinine clearance less than 10 mL/min, the elimination half-life of PEPCID may exceed 20 hours, reaching approximately 24 hours in anuric patients. Although no relationship of adverse effects to high plasma levels has been established, to avoid excess accumulation of the drug, the dose of PEPCID may be reduced to 20 mg h.s. or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response. Based on the comparison of pharmacokinetic parameters for PEPCID in adults and pediatric patients, dosage adjustment in pediatric patients with severe renal insufficiency should be considered. HOW SUPPLIED No. 3535 — PEPCID Tablets, 20 mg, are beige colored, U-shaped, film-coated tablets coded MSD 963 on one side and PEPCID on the other. They are supplied as follows: NDC 0006-0963-31 unit of use bottles of 30 NDC 0006-0963-94 unit of use bottles of 90 NDC 0006-0963-58 unit of use bottles of 100 NDC 0006-0963-28 unit dose package of 100 NDC 0006-0963-82 bottles of 1,000 NDC 0006-0963-87 bottles of 10,000 NDC 0006-0963-72 carton of 25 UNIBLISTER™ cards of 31 tablets each. No. 3536 — PEPCID Tablets, 40 mg, are light brownish-orange, U-shaped, film-coated tablets coded MSD 964 on one side and PEPCID on the other. They are supplied as follows: NDC 0006-0964-31 unit of use bottles of 30 NDC 0006-0964-94 unit of use bottles of 90 NDC 0006-0964-58 unit of use bottles of 100 NDC 0006-0964-28 unit dose package of 100 NDC 0006-0964-82 bottles of 1,000 NDC 0006-0964-87 bottles of 10,000 NDC 0006-0964-72 carton of 25 UNIBLISTER™ cards of 31 tablets each. No. 3553 — PEPCID RPD Orally Disintegrating Tablets, 20 mg, are pale rose colored, hexagonal-shaped, lyophilized tablets measuring 13.1 mm (side to side) and 15.2 mm (point to point), with a mint flavor. They are supplied as follows: NDC 0006-3553-31 unit dose package of 30 NDC 0006-3553-48 unit dose package of 100 NDC 0006-3553-28 unit dose package of 100. No. 3554 — PEPCID RPD Orally Disintegrating Tablets, 40 mg, are pale rose colored, hexagonal-shaped, lyophilized tablets measuring 15.9 mm (side to side) and 18.4 mm (point to point), with a mint flavor. They are supplied as follows: NDC 0006-3554-31 unit dose package of 30 NDC 0006-3554-48 unit dose package of 100. No. 3538 — PEPCID for Oral Suspension is a white to off-white powder containing 400 mg of famotidine for constitution. When constituted as directed, PEPCID for Oral Suspension is a smooth, mobile, off-white, homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine per 5 mL. NDC 0006-3538-92, bottles containing 400 mg famotidine. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NDAs 19-462, 19-527, 20-752 Page 12 Storage Store PEPCID Tablets and PEPCID RPD Orally Disintegrating Tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Store PEPCID for Oral Suspension dry powder and suspension at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Suspension: Protect from freezing. Discard unused suspension after 30 days. PEPCID (famotidine) Tablets and PEPCID (famotidine) for Oral Suspension are manufactured by: PEPCID RPD (famotidine) Orally Disintegrating Tablets are manufactured for: By: Scherer DDS, Swindon, England and are Made in England Issued May 2000 Printed in USA This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda	custom-source	2025-02-12T13:45:25.044369	{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19462lbl.pdf', 'application_number': 19462, 'submission_type': 'ORIG ', 'submission_number': 1}

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